Contact lens with a hydrophilic layer

ABSTRACT

Embodiments of the technology relate to a contact lens having a core that is covalently coated by a hydrogel layer, and to methods of making such a lens. In one aspect, embodiments provide for a coated contact lens comprising a lens core comprising an outer surface; and a hydrogel layer covalently attached to at least a portion of the outer surface, the hydrogel layer adapted to contact an ophthalmic surface, wherein the hydrogel layer comprises a hydrophilic polymer population having a first PEG species and a second PEG species, the first PEG species being at least partially cross-linked to the second PEG species.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional patent applicationsof Havenstrite, et al., including App. No. 61/693,689 as filed on Aug.27, 2012, App. No. 61/800,835, as filed on Mar. 15, 2013, and App. No.61/800,959, as filed on Mar. 15, 2013, each application entitled“Multilayered Contact Lens,” which are each herein incorporated byreference in its entirety. This application also claims priority to U.S.Provisional patent application of Havenstrite, et al., App. No.61/834,813 as filed on Jun. 13, 2013, entitled “Contact Lens with aHydrophilic Layer,” which is herein incorporated by reference in itsentirety.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

FIELD

Embodiments of the technology relate to a contact lens with improvedbiocompatibility and wearability and methods for making the improvedlens. More particularly, the technology relates to a contact lens with ahighly stable hydrogel layer covering a lens core.

BACKGROUND

Contact lenses are medical devices that are placed in contact with theocular surface and are used for vision correction, aesthetic purposes,and to treat ocular pathologies. Substances and materials can bedeposited onto a contact lens's surface to improve the biocompatibilityof the lens and therefore improve the interaction of the lens with theocular region.

The current generation of contact lenses commonly includes a siliconecontaining core material. These lenses have many advantages over theirrigid plastic predecessors. For example, silicone-containing lenses arebiocompatible for the eye and have improved oxygen and fluidpermeability for normal ocular surface health. However, despite theseadvantages, a major challenge for silicone-containing lenses is thehydrophobicity of silicone containing materials, which can lead toabrasion of ocular tissue and infection. As such, embodiments describedherein provide for a contact lens having improved hydrophilicity andbiocompatibility as well as practical and cost-effective methods formaking these lenses.

An additional challenge with current contact lens technology is thetendency for protein binding and absorption at the ocular site. Forexample, a contact lens may bind proteins on the lens to create proteindeposits in the eye area. Additionally, the lens can cause structuralchanges including protein denaturation that can elicit an immuneresponse such as tearing, reddening, or swelling in the ocular region.Accordingly, contemplated embodiments provide for contact lenses andmethods of making lenses with improved resistance to undesirable proteininteractions at the ocular site.

A further concern with contact lens use is that some users experiencediscomfort that is similar to the profile of patients that have a dryeye disease. Dry eye disease is considered to be a consequence of adisruption of the tear film that covers the surface of the eye, or aparticular vulnerability to such disruption. This tear film is anaqueous layer disposed between an underlying mucous layer that issecreted by corneal cells, and an overlying lipid layer that is secretedby Meibomian glands on the conjunctival surface of the eyelids. The tearfilm includes an aqueous pool that transits across the eye surface,having a flow path that, to some degree, may be independent of the lipidlayers that it is disposed between at any point in time.

Integrity of the tear film is important for such critical functions asoxygen and ion transport, and lubricating the eye surface, which issubject to a constant sliding contact by the eyelids. It is likely thatdry eye disease actually exists as a spectrum of tear film vulnerabilityto disruption. In some cases, patients may have a low-level dry eyedisease that manifests when the integrity of the film is challenged bythe presence of a contact lens. To address this concern, someembodiments of the invention provide for contact lens technology thatdiminishes or substantially eliminates contact lens disruption of thetear film.

As can be appreciated, dry eye disease may be referred to herein as anon-limiting example for illustration purposes. The methods and devicesdescribed may be used to treat or prevent other ocular pathologiesincluding, but not limited to, glaucoma, corneal ulcers, scleritis,keratitis, iritis, and corneal neovascularization.

SUMMARY OF THE DISCLOSURE

Some embodiments of the invention provide for a coated contact lensincluding a lens core comprising an outer surface and a hydrogel layercovalently attached to at least a portion of the outer surface, thehydrogel layer adapted to contact an ophthalmic surface, wherein thehydrogel layer comprises a hydrophilic polymer population having a firstPEG species and a second PEG species, the first PEG species being atleast partially cross-linked to the second PEG species.

In any of the preceding embodiments, the hydrogel layer and core arecovalently attached at the outer surface by a sulfonyl moiety. In any ofthe preceding embodiments, the hydrogel layer and core are covalentlyattached at the outer surface by an alkylene sulfonyl moiety. In any ofthe preceding embodiments, the hydrogel layer and core are covalentlyattached at the outer surface by a dialkylene sulfonyl moiety. In any ofthe preceding embodiments, the hydrogel layer and core are covalentlyattached at the outer surface by an ethylene sulfonyl moiety. In any ofthe preceding embodiments, the hydrogel layer and core are covalentlyattached at the outer surface by a diethylene sulfonyl moiety.

In any of the preceding embodiments, the hydrogel layer and core arecovalently attached at the outer surface by a thioether moiety. In anyof the preceding embodiments, the hydrogel layer and core are covalentlyattached at the outer surface by a sulfonyl moiety and a thioethermoiety.

In any of the preceding embodiments, the first PEG species comprises areactive sulfonyl group and the second PEG species comprises a reactivethiol, and the first PEG species and second PEG species are cross-linkedby a thioether linkage.

In any of the preceding embodiments, the hydrogel layer substantiallysurrounds the outer surface of the core.

In any of the preceding embodiments, the hydrogel layer and core aresubstantially optically clear. In any of the preceding embodiments, thehydrogel layer is adapted to allow optical transmission through thehydrogel layer to the ophthalmic surface.

In any of the preceding embodiments, the hydrogel layer comprises athickness between about 50 nm to about 500 nm. In any of the precedingembodiments, the hydrogel layer comprises a thickness below about 100nm. In any of the preceding embodiments, the hydrogel layer comprises amaximum thickness of about 10 microns.

In any of the preceding embodiments, a first portion of the hydrogellayer comprises a first thickness different from a second thickness of asecond portion of the hydrogel layer.

In any of the preceding embodiments, each of the first and second PEGspecies is a branched species having a branch count between two totwelve branch arms.

In any of the preceding embodiments, the first PEG species comprises areactive electron pair accepting group and the second PEG speciescomprises a reactive nucleophilic group, the reactive electron pairaccepting group and the reactive nucleophilic group adapted to react tothereby form cross-links between the first PEG species to the second PEGspecies. In any of the preceding embodiments, the reactive electron pairaccepting group is a sulfone moiety. In any of the precedingembodiments, the reactive nucleophilic group is a thiol moiety.

In any of the preceding embodiments, the reactive electron pairaccepting group of the first PEG species is covalently linked to theouter surface of the core.

In any of the preceding embodiments, the coated lens includes anadvancing contact angle between about 20 degrees to about 50 degrees. Insome embodiments, the advancing contact angle is between about 25degrees to about 35 degrees.

In any of the preceding embodiments, the hydrogel layer comprisesbetween about 80% to about 98% water by weight.

In any of the preceding embodiments, the core consists of silicone. Inany of the preceding embodiments, the core comprises silicone. In any ofthe preceding embodiments, the core is substantially free of silicone.In any of the preceding embodiments, the core comprises a hydrogel.

Another aspect of the invention relates to a multi-layer contact lensincluding a lens core layer covered by an outer hydrophilic PEG polymerlayer, wherein the hydrophilic polymer layer comprises a first PEGmacromer subpopulation having an electron pair accepting moiety and asecond PEG macromer subpopulation having a first nucleophilic reactivemoiety, wherein the first and second PEG macromer subpopulations arecross-linked.

In any of the preceding embodiments, the hydrophilic polymer layer isattached to the core layer by a covalent linkage between the electronpair accepting moiety of the first PEG macromer and a secondnucleophilic reactive moiety on a surface of the core layer. In any ofthe preceding embodiments, the covalent linkage between the core layerand the electron pair accepting moiety is a thioether moiety. In any ofthe preceding embodiments, the concentration of the electron pairaccepting moiety exceeds the concentration of the first nucleophilicreactive moiety by about 1% to about 30%. In any of the precedingembodiments, the concentration of the electron pair accepting moietyexceeds the concentration of the first nucleophilic reactive moiety byabout 5% to about 20%.

In any of the preceding embodiments, the electron pair accepting moietyis a sulfonyl group. In any of the preceding embodiments, the firstnucleophilic reactive moiety is a thiol group.

In any of the preceding embodiments, the hydrophilic polymer layercomprises one or more species of a branched PEG polymer. In any of thepreceding embodiments, the branched PEG polymer species comprises abranch count between about two arms to about twelve arms. In any of thepreceding embodiments, the branched PEG polymer species comprisesstarred branching.

In any of the preceding embodiments, each of the first and second PEGmacromers has a molecular weight between about 1 kDa and about 40 kDa.In any of the preceding embodiments, the molecular weight is betweenabout 5 kDa and about 30 kDa.

In any of the preceding embodiments, the hydrophilic PEG layer comprisesbetween about 80% and about 98% water by weight. In any of the precedingembodiments, the hydrophilic PEG layer comprises between about 85% andabout 95% water by weight.

In any of the preceding embodiments, the hydrophilic PEG layer has athickness less than about 1 micron. In any of the preceding embodiments,the hydrophilic PEG layer has a thickness less than about 5 micron. Inany of the preceding embodiments, the hydrophilic PEG layer has amaximum thickness of about 10 microns. In any of the precedingembodiments, the hydrophilic PEG layer has a maximum thickness betweenabout 1 micron to about 5 microns. In any of the preceding embodiments,the hydrophilic PEG layer has a thickness between about 50 nm to about500 nm. In any of the preceding embodiments, the hydrophilic PEG layerhas a thickness between about 100 nm to about 250 nm.

In any of the preceding embodiments, the hydrophilic PEG layer furthercomprises at least one active agent. In any of the precedingembodiments, the at least one active agent is selected from the groupconsisting of a UV-absorbing agent, a visibility tinting agent, anantimicrobial agent, a bioactive agent, a leachable lubricant, aleachable tear-stabilizing agent, or any mixture thereof.

Another aspect of the invention relates to a method of making a PEGhydrogel coated contact lens including the steps of reacting an outersurface of the contact lens with a first PEG species of a hydrophilicpolymer solution, wherein the first PEG species comprises an electronpair accepting moiety and a first portion of the electron pair acceptingmoiety forms a covalent attachment to the outer surface of the contactlens through a first nucleophilic conjugate reaction; and reacting thefirst PEG species of the hydrophilic polymer solution with a second PEGspecies of the hydrophilic polymer solution, the second PEG speciescomprising a nucleophilic reactive moiety adapted to covalently link toa second portion of the electron pair accepting moiety of the first PEGspecies in a second nucleophilic conjugate reaction to thereby at leastpartially cross-link the first and second PEG species, wherein a PEGhydrogel coating is formed and covalently attached to the outer surfaceof the contact lens by the first and second nucleophilic conjugatereactions.

In any of the preceding embodiments, further including the step ofmodifying an outer surface of a contact lens to form the plurality ofreactive nucleophilic sites on the outer surface. In any of thepreceding embodiments, the modifying step comprises exposing the outersurface of the contact lens to a gas plasma treatment.

In any of the preceding embodiments, the step of reacting an outersurface of the contact lens with the first PEG species includes reactingat least a portion of the plurality of reactive nucleophilic sites onthe outer surface with the first portion of the electron pair acceptingmoiety on the first PEG species.

In any of the preceding embodiments, both of the first and secondnucleophilic conjugate reactions are 1,4-nucleophilic additionreactions.

In any of the preceding embodiments, the first and second nucleophilicconjugate reactions are both a Michael-type reaction.

In any of the preceding embodiments, both of the first and secondnucleophilic conjugate reactions are click reactions.

In any of the preceding embodiments, the nucleophilic reactive moiety ofthe second PEG species is a thiol group and the electron pair acceptingmoiety of the first PEG species is a sulfone group.

In any of the preceding embodiments, the first PEG species and thesecond PEG species are cross-linked through a thioether moiety.

In any of the preceding embodiments, the hydrophilic polymer solutioncomprises substantially equivalent concentrations of the first andsecond PEG species.

In any of the preceding embodiments, the concentration of the electronpair accepting moiety of the first PEG species exceeds the concentrationof the nucleophilic reactive moiety of the second PEG species by about1% to about 30%. In any of the preceding embodiments, the concentrationof the electron pair accepting moiety of the first PEG species exceedsthe concentration of the nucleophilic PEG reactive moiety of the secondPEG species by about 5% and about 20%.

In any of the preceding embodiments, the reacting steps are performed ata temperature between about 15 degrees Celsius and about 100 degreesCelsius. In any of the preceding embodiments, the reacting steps areperformed at a temperature between about 20 degrees Celsius and about 40degrees Celsius. In any of the preceding embodiments, the reacting stepsare performed at a pH between about 7 and about 11.

In any of the preceding embodiments, the contact lens comprises a coresubstantially free of silicone and includes a hydrogel core.

In an exemplary embodiment, the invention is a contact lens comprising:a silicone-containing layer and a first polyethylene glycol-containinglayer; wherein said contact lens has a layered structural configuration;the subunits of the polymer of said first polyethylene glycol-containinglayer are essentially all polyethylene glycol subunits; and the firstpolyethylene glycol-containing layer and the silicone-containing layerare covalently attached.

In an exemplary embodiment, according to the above paragraph, furthercomprising a second polyethylene glycol-containing layer; wherein thesubunits of the polymer of said second polyethylene glycol-containinglayer are essentially all polyethylene glycol subunits; and the secondpolyethylene glycol-containing layer and the silicone-containing layerare covalently attached.

In an exemplary embodiment, according to any of the above paragraphs,said contact lens comprises an anterior surface and a posterior surface,and wherein said layered structural configuration is the anteriorsurface is the first polyethylene glycol-containing layer and theposterior surface is the silicone-containing layer, or the anteriorsurface is the silicone-containing layer and the posterior surface isthe first polyethylene glycol-containing layer.

In an exemplary embodiment, according to any of the above paragraphs,said contact lens comprises an anterior surface and a posterior surface,and wherein said layered structural configuration is the anteriorsurface is the first polyethylene glycol-containing layer and theposterior surface is the second polyethylene glycol-containing layer.

In an exemplary embodiment, according to any of the above paragraphs,the invention further comprises an inner layer, wherein saidsilicone-containing layer is said inner layer.

In an exemplary embodiment, according to any of the above paragraphs,said contact lens has a contact angle of between about 10 degrees andabout 20 degrees.

In an exemplary embodiment, according to any of the above paragraphs,said first polyethylene glycol-containing layer is essentiallynon-swellable.

In an exemplary embodiment, according to any of the above paragraphs,said first polyethylene glycol-containing layer is essentiallynon-swellable and said second polyethylene glycol-containing layer isessentially non-swellable.

In an exemplary embodiment, according to any of the above paragraphs,the silicone-containing layer is substantially uniform in thickness, andthe first polyethylene glycol layer is substantially uniform inthickness.

In an exemplary embodiment, according to any of the above paragraphs,the second polyethylene glycol layer is substantially uniform inthickness, and the anterior and posterior polyethylene glycol layersmerge at the peripheral edge of the contact lens to completely enclosethe silicone-containing layer.

In an exemplary embodiment, according to any of the above paragraphs,the silicone-containing layer has an average thickness of between about1 micron and about 100 microns.

In an exemplary embodiment, according to any of the above paragraphs,the silicone-containing layer has an average thickness of between about25 microns and about 75 microns.

In an exemplary embodiment, according to any of the above paragraphs,the first polyethylene glycol layer has an average thickness of betweenabout 10 microns and about 25 microns.

In an exemplary embodiment, according to any of the above paragraphs,the second polyethylene glycol layer has an average thickness of betweenabout 1 micron and about 40 microns.

In an exemplary embodiment, according to any of the above paragraphs,the second polyethylene glycol layer has an average thickness of betweenabout 10 microns and about 25 microns.

In an exemplary embodiment, according to any of the above paragraphs,the first polyethylene glycol layer and the silicone-containing layerare covalently attached through a sulfonyl moiety.

In an exemplary embodiment, according to any of the above paragraphs,the second polyethylene glycol layer and the silicone-containing layerare covalently attached through a sulfonyl moiety.

In an exemplary embodiment, according to any of the above paragraphs,the silicone-containing layer is at least 99% silicone by weight.

In an exemplary embodiment, according to any of the above paragraphs,the silicone-containing layer is at least 80% H₂O by weight.

In an exemplary embodiment, according to any of the above paragraphs,the silicone-containing layer is lotrafilcon or balafilcon or NuSil Med6755.

In an exemplary embodiment, according to any of the above paragraphs,further comprising a UV-absorbing agent, a visibility tinting agent, anantimicrobial agent, a bioactive agent, a leachable lubricant, or aleachable tear-stabilizing agent, and mixtures thereof.

In an exemplary embodiment, according to any of the above paragraphs,said UV-absorbing agent, visibility tinting agent, antimicrobial agent,bioactive agent, leachable lubricant, or leachable tear-stabilizingagent is in the silicone-containing layer.

In an exemplary embodiment, the invention is a lens package, comprisingthe contact lens according to any of the above paragraphs, and apackaging solution.

In an exemplary embodiment, according to the above paragraph, thepackaging solution comprises a viscosity-enhancing polymer, polyethyleneglycol, mucin-like material, or a surfactant.

In an exemplary embodiment, the invention is a method of making thecontact lens according to any of the above paragraphs.

Exemplary embodiments of the technology relate to a contact lens havinga base, core, or bulk material and a hydrophilic layer attached to asurface of the bulk/core/base. In some embodiments, the core or base isa silicone-containing material such as a silicone core or a siliconesubstrate. In some embodiments, the core or base may only containsilicone-containing material. In some embodiments, the core/bulk/baseconsists of silicone-containing material. In other cases, the core orbase includes about 10% to about 20% a silicone-containing material. Infurther variations, the core/bulk/base may contain about 100% silicone.In further embodiments, the contact lens substrate may contain silicone,a hydrogel, and water. In further embodiments, the contact lenssubstrate may be made of any material not limited to asilicone-containing material.

In further embodiments, the hydrophilic layer may be formed from ahydrophilic polymer. In some variations, the hydrophilic layer is ahydrogel that includes one or more polymer networks. In some variations,the hydrogel polymer network is cross-linked. In further examples, thehydrogel is a cross-linked polyethylene glycol (PEG) network.

In additional embodiments, the contact lens core is chemically bonded tothe hydrophilic layer. For example, in some embodiments, a hydrogellayer is covalently bonded to a surface of the core. In furthervariations, the covalent bonding occurs between reactive groups in aClick reaction. In some embodiments, the reactive groups are selectedaccording to a desired thermodynamic driving force in a resultingreaction. In some cases, one or more portions of the base or core isattached to the hydrophilic layer.

Further variations provide for a contact lens with a layer ofcross-linked hydrophilic polymer (for example polyethylene glycol) onsome portion of the contact lens surface in order to improve thehydrophilicity of the contact lens surface (which in some embodimentsmay be measured as decreasing advancing contact angle) and augment theinteraction of a contact lens with an ocular region. Some device orstructure embodiments are directed to a hydrophilic polymer layer,itself, without specifically including an underlying lens core.

Additional embodiments provide for methods of forming a contact lenshaving a hydrophobic core with a hydrophilic layer. In some variations,the method includes the steps of depositing a cross-linked hydrophilicpolymer onto a surface of a contact lens and covalently attaching thecross-linked hydrophilic polymer to the contact lens surface. Furthervariations may include activating the lens surface and incubating thelens in a low concentration solution of branched hydrophilic polymers.In some embodiments, the branched hydrophilic polymers include reactivefunctional groups that are reactive to each other and to the lenssurface.

In some embodiments, the methods include forming a substantiallyoptically clear cross-linked hydrophilic polymer film on the contactlens. In some cases, the optically film improves the wettability of theunderlying contact lens, which may be a silicone-containing contact lensmaterial.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe claims that follow. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1A shows a contact lens having a concave and convex surfaces.

FIG. 1B is a cross-sectional view of an exemplary contact lens with acovalently attached cross-linked hydrogel layer.

FIG. 2 is a cross-sectional view of the contact lens shown in FIG. 1B onthe cornea.

FIGS. 3A-3B show a first polymer species and a second polymer specieswith respective reactive groups A and N.

FIGS. 4A-4B show a reaction between a sulfonyl and thiol group.

FIGS. 5A-5C show schematically a hydrophilic polymer having two speciescovalently attached to a lens core.

FIGS. 6A-6C show a captive bubble test.

FIG. 7 shows an activated lens surface.

FIG. 8 is a schematic diagram of a first and second reaction withprincipal reactants.

FIGS. 9A-9D show more details of reactants and reactions depicted inFIG. 8.

FIGS. 10A-10B are flow diagrams of exemplary methods described.

FIGS. 11A-11B show a schematic viewing of a continuously stirred tankreactor.

FIGS. 12A-12B show a method of producing lenses with bilateral hydrogellayers differing in depth or composition.

FIGS. 13A-13T shows contact angles for exemplary lens.

FIG. 14A-14J shows MATLAB code for contact angle calculation.

DETAILED DESCRIPTION

As shown in FIG. 1A, a contact lens 2 may be generally understood ashaving a body with a concave surface 4 and a convex surface 6. The lensbody may include a periphery or a perimeter 8 between the surfaces. Theperiphery may also include a circumferential edge between the surfaces.

The concave surface 4 may also be referred to as a posterior surface andthe convex surface 6 may also be referred to as an anterior surface,terms that refer to respective position when worn by a user. Inpractice, the concave surface of the lens is adapted to be worn againstor adjacent to an ophthalmic surface. When worn the concave surface maylie against a user's corneal surface 48 (see FIG. 2). The convex surfaceis outward-facing, exposed to the environment when the eye 40 is open.When the eye 40 is closed, the convex surface is positioned adjacent oragainst the inner conjunctival surface 44 of the eyelids 42 (see FIG.2).

Because the convex and concave surfaces of a lens may be placed againstor adjacent ophthalmic tissue such as the corneal surface, theproperties of the surfaces can greatly affect a user's comfort andwearability of the lens as described above. For example, the lens maydisrupt the tear film 16 of the eye 40 causing symptoms associated withdry eye. As such, embodiments described herein provide for a coatedcontact lens having a hydrophilic polymer layer applied on at least oneof the lens's surfaces to improve the lens's wettability and wearabilitywith minimal tear film disruption.

In one embodiment, the contemplated coated contact lens includes a coreor bulk material with at least one surface having a hydrophilic polymerlayer. In some cases, the hydrophilic layer is adapted for placementagainst an ophthalmic surface. The hydrophilic layer may cover a portionof the lens core surface. Alternatively, the hydrophilic layer maycompletely or substantially completely cover the core surface.

In other variations, more than one core surface has a hydrophilic layer.For example, both the concave and the convex surfaces of the lens may becoated by a hydrophilic polymer layer. Each hydrophilic layer on eitherconcave or convex surfaces may independently completely or partiallycover respective surfaces. In some cases the layer on each side of thecore form a contiguous hydrophilic layer across both surfaces.

In additional variations, the hydrophilic polymer layer is formed from across-linked hydrogel polymer network having one or more cross-linkedspecies. The hydrophilic polymer network may be partially cross-linkedor substantially fully cross-linked. In some variations, the hydrophilicpolymer is cross-linked to approximately 95% end group conversion.

Referring to FIG. 1B, a cross-section of an exemplary embodiment of acoated contact lens 10 is shown. Coated contact lens 10 includes a lenscore 18 and a hydrophilic polymer layer 20 attached to the core 18. Asshown, a hydrophilic polymer layer 20 surrounds the core 18. Both theconcave and convex surfaces 12, 14 are coated by the same hydrophilicpolymer layer 20 on both sides of the lens 18 with the hydrophilicpolymer layer 20 extending to the peripheral edge 8 of the core 10. Asshown, the outer hydrophilic layer 20 is substantially contiguousthrough or across a circumferential edge portion 18.

Referring to FIG. 2, the coated contact lens 10 of FIG. 1B is positionedin a user's eye 40. The eye 40 is shown with eye lens 46 and iris 50.The concave surface 12 of the lens 10 is disposed and centered on thecornea. The convex surface 14 of the lens 10 is directed outwardly,facing the environment when the eye 40 is open. When the eyelid 42close, the convex surface 14 is adjacent to the inner or conjunctivalsurface 44 of the eyelid 42. As the eyelids 42 open and close theconjunctival surface 44 slides across the convex surface 14 of the lens10.

When placed on the cornea, the hydrophilic layer 20 of the contact lens10 interacts with the natural tear film 16 of the eye 40. The contactlens 10 may be positioned within the tear film 16 and/or substantiallyreside within the aqueous layer of the tear film 16 that covers the eye40. In some cases, the lens 10 is immersed in the tear film 16. Thehydrophilic layer may be adapted to minimize disruption of the tear filmby the contact lens.

A. HYDROPHILIC POLYMER LAYER

As used herein, the term “hydrophilic layer” or “hydrogel layer” mayrefer to a single continuous layer or various coated portions on thelens core.

Although shown in FIG. 1B as a single hydrophilic layer covering bothsides of the lens core, it is to be appreciated that in some cases, onlya portion of the lens (e.g. a single surface or a part of a surface) maybe coated by a hydrophilic polymer layer. In some cases, the hydrophiliclayer may only coat one of the core surfaces such as the concavesurface. Moreover, the layer may not coat the entire area of thesurface.

Additionally, other contemplated embodiments may include two or morenoncontiguous hydrophilic polymer layers. For example, a firsthydrophilic polymer layer may at least partially cover the concavesurface while a second hydrophilic polymer layer may at least partiallycover the convex surface. Unlike the embodiment depicted in FIG. 1B, thefirst and second hydrophilic polymer layer may not touch or share aboundary with one another.

In certain embodiments, the arrangement between the lens core and thesurrounding hydrogel or hydrophilic layer may be understood as a layeredstructure with a hydrophilic polymer layer attached to an outer surfaceof a lens core layer. The hydrophilic polymer layer may be placed oneither of the concave or convex surfaces. In some variations, thehydrophilic layer may only cover a portion of the lens core layer.

In other cases, the arrangement may include a first hydrophilic polymerlayer on one side of the lens core layer, a second hydrophilic polymerlayer on another side of the lens core layer. The core layer being amiddle layer between the two hydrophilic polymer layers. The first andsecond layers may share a boundary (e.g. contiguous layers) or may formseparate independent layers (e.g. noncontiguous layers).

In some cases, the layered arrangement a contact lens of the inventioncan be established by fluorescence analysis methods as described in Quiet al, U.S. Pat. Appl. Nos. 201200026457 and 201200026458.

Additionally, the hydrophilic layer may have relatively uniformdimensions, compositions, and mechanical properties throughout.Referring to FIG. 1B, the hydrophilic layer 20 has a substantiallyuniform thickness, water content, and chemical composition throughoutthe layer. In some embodiments, the hydrophilic layer has asubstantially homogeneous composition and a substantially uniform depthand/or thickness.

As can be appreciated, uniformity is not required and may not bedesirable for all situations. In some cases, a single layer may includeportions having different characteristics including dimensions,composition, and/or mechanical properties. For example, a portion of thelayer may have a different thickness than another portion, which mayresult in varying water content between the two portions.

Similarly, where two or more hydrophilic layers are used, thehydrophilic polymer layers may share or differ in any characteristics.For example, the core material may be asymmetrically layered with thehydrophilic polymer. The depth/thickness of the resulting hydrophilicpolymer layers may vary between the layers on opposing sides of the lenssubstrate. This can result in, for example, different mechanicalcharacteristics between the concave-cornea facing side of the coatedcontact lens and the outward facing convex face.

In some variations, the average thickness of the hydrophilic polymerlayer may range between about 50 nm and about 500 nm. In particularembodiments, the hydrophilic layer has a thickness of about 100 nm toabout 250 nm. In an exemplary embodiment, the thickness of thehydrophilic layer is between about 1 micron and about 200 microns, orbetween about 1 micron and about 100 microns, or between about 10microns and about 200 microns, or between about 25 microns and about 200microns, or between about 25 microns and about 100 microns, or betweenabout 5 microns and about 50 microns, or between about 10 microns andabout 50 microns, or between about 10 microns and about 35 microns, orbetween about 10 microns and about 25 microns, or between about 1 micronand about 10 microns.

In other embodiments, hydrophilic layer has a thickness between about0.01 microns and about 1 micron, or between about 0.01 microns and about0.05 microns, or between about 0.05 microns and about 1 micron, orbetween about 0.02 microns and about 0.04 microns, or between about0.025 microns and about 0.075 microns, or between about 0.02 microns andabout 0.06 microns, or between about 0.03 microns and about 0.06microns. In an exemplary embodiment, the hydrophilic layer has anaverage thickness of between about 0.01 microns and about 25 microns, orbetween about 0.01 microns and about 20 microns, or between about 0.01microns and about 15 microns, or between about 0.01 microns and about 10microns, or between about 0.01 microns and about 5 microns, or betweenabout 0.01 microns and about 2.5 microns, or between about 0.01 micronsand about 2 microns. In other variations, the hydrophilic layer has anaverage thickness from about 0.1 microns to about 20 microns, or fromabout 0.25 microns to about 15 microns, or from about 0.5 microns toabout 12.5 microns, or from about 2 microns to about 10 microns.

In further variations, the thickness or depth of the hydrogel layer mayalso be expressed in terms of the fold-multiple over a layer that couldbe represented as a molecular monolayer. In some embodiments, thehydrophilic layer has a thickness of that exceeds the nominal thicknessof a molecular monolayer by at least five-fold. For example, in somecases the hydrophilic polymer layer is formed from PEG molecules thathave a PEG monolayer radius of about 5 nm. The PEG containinghydrophilic polymer layer may have a thickness of about 50 nm, whichresults in a layer thickness or depth that is approximately 10-foldgreater than the PEG monolayer radius.

Without limitation, the thickness of the anterior or posterior surfaceof a contact lens of the invention can be determined by AFM orfluorescence microscopy analysis of a cross section of the contact lensin fully hydrated state as described herein. In an exemplary embodiment,the thickness of the anterior or posterior surface is at most about 30%(i.e., 30% or less), or at most about 20% (20% or less), or at mostabout 10% (10% or less) of the thickness of the inner layer (e.g. core)of the contact lens described in a fully hydrated state. In an exemplaryembodiment, the layers forming the anterior and posterior surface of thecontact lens described in this paragraph are substantially uniform inthickness. In an exemplary embodiment, these layers merge at theperipheral edge of the contact lens to completely enclose the innerlayer of the silicon-containing layer.

Additionally, the hydrophilic layer may be understood to have a volume.In some cases, a first portion of the layer may have first volume V1 anda second portion of the layer may have a second volume V2. The volumemay be calculated based on an estimated surface area of the layer. Atotal volume may also be understood to be the volume of a singlehydrophilic layer (e.g. a layer covering the entire lens) or a sum ofvarious layers with corresponding volumes.

Volume calculations may be based on an estimated surface area ofapproximately 1.25 square centimeters, on each side of the lens core. Insome cases, the hydrophilic polymer layer has a volume in the range ofabout 15 nl to about 1.5 μl. In other variations, a volume range ofabout 15 nl to about 150 nl corresponds to an enveloping hydrophilicthickness range of about 50 nm to about 500 nm.

Additionally, in some variations, the hydrophilic layer may host anaqueous pool that includes a portion of the tear film pool volume. Thetotal volume of the tear film is estimated to be about 4 μl to about 10μl. For the purpose of the following calculation, consider an estimatedof total tear film volume of about 7.5 μl. Accordingly, in someembodiments, the hydrophilic layer may host an aqueous pool thatcomprises about from about 0.2% to about 2% of the total tear film poolvolume

For water content of the hydrophilic layer, in some embodiments, thewater content is between about 80% and about 98% water by weight. Inother embodiments, the hydrophilic layer includes between about 85% andabout 95% water by weight. Additionally, the water content of thehydrophilic layer may be expressed either by total water content or by aweight/volume percent. The polymer content of the hydrophilic layer maybe described also by a weight/volume percent.

The hydrophilic layer may also include a hydrophilic polymer populationhaving one or more subpopulations or species. In some cases, one or morespecies or subpopulations are cross-linked to form the hydrophilicpolymer layer. The hydrophilic polymer layer precursors may be providedin a solution containing the cross-linkable material. Once cross-linked,the one or more species form the hydrophilic polymer coating.

In one variation, the hydrophilic layer includes a first polymer speciesand a second polymer species that are at least partially cross-linkedtogether to form the hydrophilic layer. Additionally, the polymerspecies or subpopulation may include linear and/or branched components.A branched species may include a polymer having a branch count rangingfrom 2-arm to 12-arm branching. In other embodiments, the branchedspecies may include starred branching with about 100 branches or more.

Referring to the FIG. 3A, a first branched polymer species 51 and asecond branched polymer species 52 are schematically shown. The firstbranched polymer species 51 has four branch arms with reactivefunctional group A. The second branched polymer species 52 is shownhaving four branch arms with a reactive functional group N. In someembodiments, a reactive moiety A of the first polymer species 51 isadapted to react with a reactive moiety B of the second polymer species52. The reaction between moieties A and B may form a covalent cross-linkbetween the first and second polymer species. FIG. 3B depicts the firstand second species 51, 52 cross-linked by an A-N moiety formed by areaction between the reactive group A of the first polymer species and areactive group B of a second polymer species. In some embodiments, thecross-linking action between one or more polymer and/or macromer speciesforms the hydrophilic polymer layer. For example, cross-linking one ormore polymer species in a polymer solution may form a hydrogel withdesirable characteristics for coating the lens core.

As can be appreciated, the cross-linking mechanism and/or reaction for afirst and second polymer species may include any number of suitablemethods known in the art including photochemical or thermalcross-linking. In some cases, cross-linking may occur throughnucleophilic conjugate reaction, Michael-type reaction (e.g. 1,4addition), and/or Click reaction between respective reactive groups onmore than one polymer species in the hydrophilic layer.

Any suitable polymers may be used for the hydrophilic polymer populationin the hydrophilic layer. In some cases, the polymer population includesspecies derived from polyethylene glycol (PEG), phosphorylcholine,poly(vinyl alcohol), poly(vinylpyrrolidinone),poly(N-isopropylacrylamide) (PNIPAM), polyacrylamide (PAM),poly(2-oxazoline), polyethylenimine (PEI), poly(acrylic acid), acrylicpolymers such as polymethacrylate, polyelectrolytes, hyaluronic acid,chitosan, and dextran.

Additionally, any suitable reactive moieties may be used for the polymerspecies and subpopulations including reactive functional groups (e.g.reactive nucleophilic groups and electron pair acceptor) that react toform covalent linkages between polymer species or subpopulations to formthe hydrophilic polymer layer described.

1. Reactive Functional Groups

Reactive functional groups and classes of reactions useful in covalentlinking and cross-linking are generally known in the art. In some cases,suitable classes of reactions with reactive functional groups includethose that proceed under relatively mild conditions. These include, butare not limited to nucleophilic substitutions (e.g., reactions of aminesand alcohols with acyl halides and activated esters), electrophilicsubstitutions (e.g., enamine reactions) and additions to carbon-carbonand carbon-heteroatom multiple bonds (e.g., Michael reactions andDiels-Alder reactions). These and other useful reactions are discussed,for example, in: March, ADVANCED ORGANIC CHEMISTRY, 3rd Ed., John Wiley& Sons, New York, 1985; Hermanson, BIOCONJUGATE TECHNIQUES, AcademicPress, San Diego, 1996; and Feeney et al., MODIFICATION OF PROTEINS;Advances in Chemistry Series, Vol. 198, American Chemical Society,Washington, D.C., 1982.

a) Amines and Amino-Reactive Groups

In one embodiment, the reactive functional group is a member selectedfrom amines, such as a primary or secondary amine, hydrazines,hydrazides, and sulfonylhydrazides. Amines can, for example, beacylated, alkylated or oxidized. Useful non-limiting examples ofamino-reactive groups include N-hydroxysuccinimide (NHS) esters,sulfo-NHS esters, imidoesters, isocyanates, isothiocyanates,acylhalides, arylazides, p-nitrophenyl esters, aldehydes, sulfonylchlorides and carboxyl groups.

NHS esters and sulfo-NHS esters react preferentially with the primary(including aromatic) amino groups of the reaction partner. The imidazolegroups of histidines are known to compete with primary amines forreaction, but the reaction products are unstable and readily hydrolyzed.The reaction involves the nucleophilic attack of an amine on the acidcarboxyl of an NHS ester to form an amide, releasing theN-hydroxysuccinimide.

Imidoesters are the most specific acylating reagents for reaction withthe amine groups of e.g., a protein. At a pH between 7 and 10,imidoesters react only with primary amines. Primary amines attackimidates nucleophilically to produce an intermediate that breaks down toamidine at high pH or to a new imidate at low pH. The new imidate canreact with another primary amine, thus crosslinking two amino groups, acase of a putatively monofunctional imidate reacting bifunctionally. Theprincipal product of reaction with primary amines is an amidine that isa stronger base than the original amine. The positive charge of theoriginal amino group is therefore retained. As a result, imidoesters donot affect the overall charge of the conjugate.

Isocyanates (and isothiocyanates) react with the primary amines of theconjugate components to form stable bonds. Their reactions withsulfhydryl, imidazole, and tyrosyl groups give relatively unstableproducts.

Acylazides are also used as amino-specific reagents in whichnucleophilic amines of the reaction partner attack acidic carboxylgroups under slightly alkaline conditions, e.g. pH 8.5.

Arylhalides such as 1,5-difluoro-2,4-dinitrobenzene react preferentiallywith the amino groups and phenolic groups of the conjugate components,but also with its sulfhydryl and imidazole groups.

p-Nitrophenyl esters of carboxylic acids are also useful amino-reactivegroups. Although the reagent specificity is not very high, α- andε-amino groups appear to react most rapidly.

Aldehydes react with primary amines of the conjugate components.Although unstable, Schiff bases are formed upon reaction of the aminogroups with the aldehyde. Schiff bases, however, are stable, whenconjugated to another double bond. The resonant interaction of bothdouble bonds prevents hydrolysis of the Schiff linkage. Furthermore,amines at high local concentrations can attack the ethylenic double bondto form a stable Michael addition product. Alternatively, a stable bondmay be formed by reductive amination.

Aromatic sulfonyl chlorides react with a variety of sites of theconjugate components, but reaction with the amino groups is the mostimportant, resulting in a stable sulfonamide linkage.

Free carboxyl groups react with carbodiimides, soluble in both water andorganic solvents, forming pseudoureas that can then couple to availableamines yielding an amide linkage. Yamada et al., Biochemistry 1981, 20:4836-4842, e.g., teach how to modify a protein with carbodiimides.

b) Sulfhydryl and Sulfhydryl-Reactive Groups

In another embodiment, the reactive functional group is a memberselected from a sulfhydryl group (which can be converted to disulfides)and sulfhydryl-reactive groups. Useful non-limiting examples ofsulfhydryl-reactive groups include maleimides, alkyl halides, acylhalides (including bromoacetamide or chloroacetamide), pyridyldisulfides, and thiophthalimides.

Maleimides react preferentially with the sulfhydryl group of theconjugate components to form stable thioether bonds. They also react ata much slower rate with primary amino groups and imidazole groups.However, at pH 7 the maleimide group can be considered asulfhydryl-specific group, since at this pH the reaction rate of simplethiols is 1000-fold greater than that of the corresponding amine.

Alkyl halides react with sulfhydryl groups, sulfides, imidazoles, andamino groups. At neutral to slightly alkaline pH, however, alkyl halidesreact primarily with sulfhydryl groups to form stable thioether bonds.At higher pH, reaction with amino groups is favored.

Pyridyl disulfides react with free sulfhydryl groups via disulfideexchange to give mixed disulfides. As a result, pyridyl disulfides arerelatively specific sulfhydryl-reactive groups.

Thiophthalimides react with free sulfhydryl groups to also formdisulfides.

c) Other Reactive Functional Groups

Other exemplary reactive functional groups include:

-   -   (a) carboxyl groups and various derivatives thereof including,        but not limited to, N-hydroxybenztriazole esters, acid halides,        acyl imidazoles, thioesters, p-nitrophenyl esters, alkyl,        alkenyl, alkynyl and aromatic esters;    -   (b) hydroxyl groups, which can be converted to esters, ethers,        aldehydes, etc.;    -   (c) haloalkyl groups, wherein the halide can be displaced with a        nucleophilic group such as, for example, an amine, a carboxylate        anion, thiol anion, carbanion, or an alkoxide ion, thereby        resulting in the covalent attachment of a new group at the site        of the halogen atom;    -   (d) dienophile groups, which are capable of participating in        Diels-Alder reactions such as, for example, maleimido groups;    -   (e) aldehyde or ketone groups, such that subsequent        derivatization is possible via formation of carbonyl derivatives        such as, for example, imines, hydrazones, semicarbazones or        oximes, or via such mechanisms as Grignard addition or        alkyllithium addition;    -   (f) alkenes, which can undergo, for example, cycloadditions,        acylation, Michael addition, etc;    -   (g) epoxides, which can react with, for example, amines and        hydroxyl groups;    -   (h) phosphoramidites and other standard functional groups useful        in nucleic acid synthesis and    -   (i) any other functional group useful to form a covalent bond        between the functionalized ligand and a molecular entity or a        surface.        d) Reactive Functional Groups with Non-Specific Reactivities

In addition to the use of site-specific reactive moieties, the presentinvention contemplates the use of non-specific reactive functionalgroups. Non-specific groups include photoactivatable groups, forexample. Photoactivatable groups are ideally inert in the dark and areconverted to reactive species in the presence of light. In oneembodiment, photoactivatable groups are selected from macromers ofnitrenes generated upon heating or photolysis of azides.Electron-deficient nitrenes are extremely reactive and can react with avariety of chemical bonds including N—H, O—H, C—H, and C═C. Althoughthree types of azides (aryl, alkyl, and acyl derivatives) may beemployed, arylazides are presently preferred. The reactivity ofarylazides upon photolysis is better with N—H and O—H than C—H bonds.Electron-deficient arylnitrenes rapidly ring-expand to formdehydroazepines, which tend to react with nucleophiles, rather than formC—H insertion products. The reactivity of arylazides can be increased bythe presence of electron-withdrawing substituents such as nitro orhydroxyl groups in the ring. Such substituents push the absorptionmaximum of arylazides to longer wavelength. Unsubstituted arylazideshave an absorption maximum in the range of 260-280 nm, while hydroxy andnitroarylazides absorb significant light beyond 305 nm. Therefore,hydroxy and nitroarylazides may be preferable since they allow to employless harmful photolysis conditions for the affinity component thanunsubstituted arylazides.

In an exemplary embodiment, photoactivatable groups are selected fromfluorinated arylazides. The photolysis products of fluorinatedarylazides are arylnitrenes, all of which undergo the characteristicreactions of this group, including C—H bond insertion, with highefficiency (Keana et al., J. Org. Chem. 55: 3640-3647, 1990).

In another embodiment, photoactivatable groups are selected frombenzophenone residues. Benzophenone reagents generally give highercrosslinking yields than arylazide reagents.

In another embodiment, photoactivatable groups are selected from diazocompounds, which form an electron-deficient carbene upon photolysis.These carbenes undergo a variety of reactions including insertion intoC—H bonds, addition to double bonds (including aromatic systems),hydrogen attraction and coordination to nucleophilic centers to givecarbon ions.

In still another embodiment, photoactivatable groups are selected fromdiazopyruvates. For example, the p-nitrophenyl ester of p-nitrophenyldiazopyruvate reacts with aliphatic amines to give diazopyruvic acidamides that undergo ultraviolet photolysis to form aldehydes. Thephotolyzed diazopyruvate-modified affinity component will react likeformaldehyde or glutaraldehyde.

It is well within the abilities of a person skilled in the art to selecta reactive functional group, according to the reaction partner. As anexample, an activated ester, such as an NHS ester can be a usefulpartner with a primary amine. Sulfhydryl reactive groups, such asmaleimides can be a useful partner with SH, thiol, groups.

Additional exemplary combinations of reactive functional groups found ona compound of the invention and on a targeting moiety (or polymer orlinker) are set forth in Table 1.

TABLE 1 Chemical Chemical Functionality 1 Functionality 2 LinkageHydroxy Carboxy Ester Hydroxy Carbonate Amine Carbamate SO₃ Sulfate PO₃Phosphate Carboxy Acyloxyalkyl Ketone Ketal Aldehyde Acetal HydroxyAnhydride Mercapto Mercapto Disulfide Carboxy Acyloxyalkyl ThioetherCarboxy Thioester Carboxy Amino amide Mercapto Thioester CarboxyAcyloxyalkyl ester Carboxy Acyloxyalkyl amide Amino Acyloxyalkoxycarbonyl Carboxy Anhydride Carboxy N-acylamide Hydroxy Ester HydroxyHydroxymethyl ketone ester Hydroxy Alkoxycarbonyl oxyalkyl Amino CarboxyAcyloxyalkylamine Carboxy Acyloxyalkylamide Amino Urea Carboxy AmideCarboxy Acyloxyalkoxycarbonyl Amide N-Mannich base Carboxy Acyloxyalkylcarbamate Phosphate Hydroxy Phosphate oxygen ester Amine PhosphoramidateMercapto Thiophosphate ester Ketone Carboxy Enol ester SulfonamideCarboxy Acyloxyalkyl sulfonamide Ester N-sulfonyl-imidate

One skilled in the art will readily appreciate that many of theselinkages may be produced in a variety of ways and using a variety ofconditions. For the preparation of esters, see, e.g., March supra at1157; for thioesters, see, March, supra at 362-363, 491, 720-722, 829,941, and 1172; for carbonates, see, March, supra at 346-347; forcarbamates, see, March, supra at 1156-57; for amides, see, March supraat 1152; for ureas and thioureas, see, March supra at 1174; for acetalsand ketals, see, Greene et al. supra 178-210 and March supra at 1146;for acyloxyalkyl derivatives, see, PRODRUGS: TOPICAL AND OCULAR DRUGDELIVERY, K. B. Sloan, ed., Marcel Dekker, Inc., New York, 1992; forenol esters, see, March supra at 1160; for N-sulfonylimidates, see,Bundgaard et al., J. Med. Chem., 31:2066 (1988); for anhydrides, see,March supra at 355-56, 636-37, 990-91, and 1154; for N-acylamides, see,March supra at 379; for N-Mannich bases, see, March supra at 800-02, and828; for hydroxymethyl ketone esters, see, Petracek et al. Annals NYAcad. Sci., 507:353-54 (1987); for disulfides, see, March supra at 1160;and for phosphonate esters and phosphonamidates.

The reactive functional groups can be chosen such that they do notparticipate in, or interfere with, the reactions necessary to assemblethe reactive ligand analogue. Alternatively, a reactive functional groupcan be protected from participating in the reaction by the presence of aprotecting group. Those of skill in the art will understand how toprotect a particular functional group from interfering with a chosen setof reaction conditions. For examples of useful protecting groups, seeGreene et al., PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, John Wiley &Sons, New York, 1991.

Generally, prior to forming the linkage between the compound of theinvention and the targeting (or other) agent, and optionally, the linkergroup, at least one of the chemical functionalities will be activated.One skilled in the art will appreciate that a variety of chemicalfunctionalities, including hydroxy, amino, and carboxy groups, can beactivated using a variety of standard methods and conditions. Forexample, a hydroxyl group of the ligand (or targeting agent) can beactivated through treatment with phosgene to form the correspondingchloroformate, or p-nitrophenylchloroformate to form the correspondingcarbonate.

In an exemplary embodiment, the invention makes use of a targeting agentthat includes a carboxyl functionality. Carboxyl groups may be activatedby, for example, conversion to the corresponding acyl halide or activeester. This reaction may be performed under a variety of conditions asillustrated in March, supra pp. 388-89. In an exemplary embodiment, theacyl halide is prepared through the reaction of the carboxyl-containinggroup with oxalyl chloride. The activated agent is combined with aligand or ligand-linker arm combination to form a conjugate of theinvention. Those of skill in the art will appreciate that the use ofcarboxyl-containing targeting agents is merely illustrative, and thatagents having many other functional groups can be conjugated to theligands of the invention.

Referring to FIG. 4A, in some embodiments, the reactive functionalgroups include thiol and sulfonyl moieties. The reactive nucleophilicgroup may be a thiol group adapted to react to a sulfonyl group thatfunctions as an electron pair accepting moiety. Where a first polymerspecies contains a reactive thiol group and a second polymer speciescontains a reactive sulfonyl group, the cross-linkage between the firstand second species may be formed through a thioether moiety (FIG. 4B).

In other variations, one or more polymer species in the hydrophiliclayer are covalently linked through a sulfonyl moiety such as, but notlimited to, an alkylene sulfonyl moiety, a dialkylene sulfonyl moiety,an ethylene sulfonyl moiety, or a diethylene sulfonyl moiety. In furthervariations, one or more polymer species in the hydrophilic layer arecovalently linked through a sulfonyl moiety and a thioether moiety, oran alkylene sulfonyl moiety and a thioether moiety, or a dialkylenesulfonyl moiety and a thioether moiety, or an ethylene sulfonyl moietyand a thioether moiety, or a diethylene sulfonyl moiety and a thioethermoiety.

In further variations, the one or more polymer species in thehydrophilic layer are covalently linked through an ester moiety, oralkylene ester moiety, or an ethylene ester moiety, or a thioethermoiety, or an ester moiety and a thioether moiety, or an alkylene estermoiety and a thioether moiety, or an ethylene ester moiety and athioether moiety.

In some embodiments, the ratio of the reactive subpopulations in thehydrophilic polymer population is approximately 1 to 1. In otherembodiments, the concentration of one of the subpopulations or speciesexceeds another species by about 10% to about 30%. For example, theconcentration of a polymer species with an electron pair acceptingmoiety may exceed another polymer species with a reactive nucleophilicgroup.

Additionally, where the concentration of a first and second polymerspecies are approximately 1 to 1, the relative number of reactivemoieties for each species may be approximately the same or different.For example, a polymer species may have more sites having an electronpair accepting moiety compared to the number of reactive sites on theother polymer species carrying the nucleophilic group. This may beaccomplished, for example, by having a first branched polymer specieshaving more arms with reactive electron pair accepting sites compared toa second polymer species carrying the nucleophilic moiety.

2. PEG-Containing Hydrophilic Layer

In some embodiments, the polymers in the hydrophilic layer comprisepolyethylene glycol (PEG). The PEG may include species that have amolecular weight of between about 1 kDa and about 40 kDa. In particularembodiments, the PEG species have a molecular weight of between about 5kDa and about 30 kDa. In some embodiments, the hydrophilic polymerpopulation consists of a species of polyethylene glycol (PEG). In othervariations, the weight average molecular weight M_(w) of the PEG polymerhaving at least one amino or carboxyl or thiol or vinyl sulfone oracrylate moiety (as a hydrophilicity-enhancing agent) can be from about500 to about 1,000,000, or from about 1,000 to about 500,000. In otherembodiments, the hydrophilic polymer population comprises differentspecies of PEG.

In some cases, the polymer includes subunits of PEG. In some variations,the subunits of the polymers of the PEG-containing layer of the contactlens are at least about 95%, or at least about 96%, or at least about97%, or at least about 98%, or at least about 99% or at least about99.5% polyethylene glycol.

In some cases, the water content of the PEG-containing hydrophilic layeris between about 80% and about 98% water by weight. In otherembodiments, the hydrophilic layer includes between about 85% and about95% water by weight.

The PEG-containing hydrophilic layer may include a PEG hydrogel having aswelling ratio. To determine swelling ratio, the PEG-hydrogel can beweighed immediately following polymerization and then immersed indistilled water for a period of time. The swollen PEG hydrogel isweighed again to determine the amount of water absorbed into the polymernetwork to determine the swelling ratio. The mass fold increase an alsobe determined based on this comparison before and after water swelling.In some embodiments, the PEG-containing layer has a mass fold increaseof less than about 10%, or of less than about 8%, or of less than about6%, or of less than about 5%, or of less than about 4%, or of less thanabout 3%, or of less than about 2%, or of less than about 1%. In somecases, the mass fold increase is measured by weighing the hydrogel whenwet and then dehydrating it and weighing it again. The mass foldincrease is then the swollen weight minus the dry weight divided by theswollen weight. For the hydrophilic layer as opposed to a bulk hydrogel,this could be accomplished by coating a non-hydrated substrate and thenperforming mass change calculations.

In another aspect, the invention provides for a hydrophilic layer withtwo cross-linkable PEG species. The first PEG species may include areactive functional group adapted to react to another reactivefunctional on the second PEG species. Any of the described functionalgroups (e.g. previous section (A)(1)) may be suitable for forming across-linkage between the first and second PEG species.

In some cases, the first PEG species includes an electron pair acceptingmoiety and the second PEG species may include a reactive nucleophilicmoiety. Once cross-linked through a reaction between the electron pairaccepting and nucleophilic moieties, the PEG polymer network forms ahydrogel with a water content or concentration. The PEG hydrogel mayserve as the hydrophilic layer coating a lens core to provide improvedwettability, wearability, and/or reduced tear film disruption.

3. Active Agents

The hydrophilic polymer layer may include active agents such as any oneor more of a medicinal agent, UV-absorbing agent, a visibility tintingagent, an antimicrobial agent, a bioactive agent, a leachable lubricant,a leachable tear-stabilizing agent, or any mixture thereof. Thesubstances and materials may be deposited on the contact lenses toaugment the interaction of a contact lens with the ocular region. Thesesubstances may consist of polymers, drugs, or any other suitablesubstance and may be used to treat a variety of ocular pathologiesincluding but not limited to dry eye disease, glaucoma, corneal ulcers,scleritis, keratitis, iritis, and corneal neovascularization.

4. Interpenetration Polymer Network

The outer hydrogel network may also consist of interpenetrating polymernetworks (or semi-interpenetrating polymer networks) formed in eithersimultaneous or sequential polymerization steps. For example, uponforming the initial outer hydrogel layer, the layer can be swollen in amonomer solution such as acrylic acid along with a crosslinker andinitiator. Upon exposure to UV light, a second interpenetrating networkwill form. The double network confers additional mechanical strength anddurability while maintaining high water content and high wettability.

B. LENS CORE

Any suitable contact lens may be used as a lens core for coating by thehydrophilic polymer layer described. For example, the lens core may behydrophobic or a hydrophilic. A hydrophilic core may have adequate watercontent but lack protein binding resistance that is imparted by thecontemplated hydrophilic layer. A hydrophilic core would include ahydrogel containing core such as a pure hydrogel lens. For example, thecore may contain Polyhexyethyl methacrylate lenses (pHEMA).

A suitable hydrophobic core includes a lens with high silicone content.The lens core may consist substantially entire of pure silicone, i.e.the core comprises about 100% silicone by weight. In other cases, thelens core, base, or substrate comprises about 10 to about 50 of siliconeby weight. In some cases, the substrate or core comprises about 25%silicone by weight.

In another embodiment, the lens core may contain a silicone-hydrogel(SiHy) where the core is more hydrophilic than a pure silicone core butless hydrophilic than a pure hydrogel. In such cases, the SiHy lens corecan be coated by the described hydrophilic polymer layers to improvewettability and wearability of the lens core. In other variations, thecore comprises about 10% to about 20% of silicone by weight.

In an exemplary embodiment, the silicone-containing layer or core of thecoated contact lens is lotrafilcon, balafilcon, galyfilcon, senofilcon,narafilcon, omafilcon, comfilcon, enfilcon, or asmofilcon. In somecases, the silicone-containing core is NuSil Med 6755.

Alternatively, a non-silicone based core may be used as the substratefor coating. For example, an oxygen permeable lens made from anon-silicone material may also be coated with the described hydrophiliclayer.

In an exemplary embodiment, the thickness of the core or core layer isfrom about 0.1 microns to about 200 microns, or from about 1 microns toabout 150 microns, or from about 10 microns to about 100 microns, orfrom about 20 microns to about 80 microns, or from about 25 microns toabout 75 microns, or from about 40 microns to about 60 microns.

C. ATTACHMENT OF HYDROPHILIC LAYER TO CORE

Another aspect of the invention provides for a coated contact lens withhydrophilic polymer layer that is covalently linked and attached to thecore. The covalent linkage between the hydrophilic layer and the coremay be understood to be a linking moiety that is covalently disposedbetween the lens core and the hydrophilic layer. In some cases, thelinking moiety covalently attaches the hydrophilic layer to an outersurface of the lens core.

In some embodiments, the linking moiety may include any of the reactivefunctional groups described in at least section (A)(1). In furthervariations, the linking moiety may be a resultant moiety formed from areaction between one or more of the reactive functional groups describedin at least section (A)(1). For example, the linking moiety may includean electron pair accepting group such as a Michael-type Michael-Typeelectron pair acceptor (e.g. sulfone group) on a polymer species in thehydrophilic layer that reacts to covalently attach the hydrophilicpolymer layer to the core.

Advantageously, the hydrophilic polymer layer may be attached to thecore through similar reactions utilized to cross-link the hydrophilicpolymer layer. Referring to FIGS. 5A-5C, the hydrophilic polymer layerincludes a first polymer species P1 having a reactive group A and secondpolymer species P2 with a reactive group N1. As described earlier, thehydrophilic polymer layer may be formed by cross-linking the firstpolymer species and the second polymer species through a reactionbetween reactive group A and N1. As shown in FIG. 5A cross-linkages 63covalently link the first and second species to form the firsthydrophilic polymer layer 70A on the convex surface 64 and the secondhydrophilic polymer layer 70B on the concave surface 62 of the lens core60.

Referring still to FIG. 5A, the first polymer species also forms acovalent linkage 61 with the outer surface of the core. As shown, thecovalent linkage is formed through the reactive group A of the firstpolymer species P1 and the core surface. In some embodiments, thereactive group A on the first polymer species P1 reacts to (1) crosslinkthe polymer species in the hydrophilic polymer layer and (2) attach theformed hydrophilic polymer layer to the core. In such cases, thispermits a first portion of the A moieties to react with the N1 moietiesand a second portion of A moieties to react with the core surface. Insome cases, the concentration of the first polymer species P1 and/or thenumber of available reactive A moieties of the first polymer speciesexceeds the corresponding concentration of the second polymer speciesand/or available reactive N1 moieties.

Referring to FIG. 5B, the lens core may include a reactive moiety N2.Reactive moiety N2 may be adapted to react with reactive groups ofpolymer species in the hydrophilic polymer layer. In some cases, thereactive moiety N2 only reacts to one of the polymer species. Referringto FIG. 5C, reactive moiety N2 reacts with reactive group A on the firstspecies P1 to form a covalent attachment between the hydrophilic polymerlayer and the core.

As can be appreciated, the reaction for attaching the hydrophilicpolymer layer to the core may include any number of suitable methodsknown in the art including those described in at least section (A)(1).In some cases, covalent linking occurs through nucleophilic conjugatereaction, Michael-type reaction (e.g. 1,4 addition), and/or Clickreaction between respective reactive groups on more than one polymerspecies in the hydrophilic layer.

In some cases, the reactive A group is an electron pair acceptor and thereactive groups N1 and N2 are reactive nucleophilic groups. N1 and N2may be the same or different reactive groups. Continuing with theexample shown in FIGS. 5A-5C, the hydrophilic polymer layer is formed bya first reaction between the reactive A group and reactive nucleophileN1. Additionally, the hydrophilic polymer layer is covalently attachedto the core through a second reaction between the reactive A group andnucleophile N2. The two reactions may occur simultaneously or nearsimultaneously in the same reaction vessel.

Where the reactive functional groups include thiol and sulfonylmoieties, the reactive A group may be a sulfonyl group on a first PEGmacromer. The sulfone moiety functions as an electron pair acceptingmoiety on the first PEG macromer. The reactive nucleophiles N1 and/or N2may be a thiol group (see FIG. 4A). For the first reaction, the firstand second PEG macromers form a cross-link through the reactive thioland sulfonyl groups, which can results in a thioether moiety (see FIG.4B). Where the N2 nucleophile on the core is also thiol, a thioether mayalso be formed by a reaction between the sulfonyl moiety on the firstPEG macromer and the N2 on the surface of the lens core.

As can be appreciated, the nucleophilic group (or other type of reactivegroup) on the core does not need to be the same as the reactive groupsin the hydrophilic polymer layers. However, utilizing the same reactivegroups may provide some advantages such as controllability andpredictability of the respective reactions.

In other variations, the hydrophilic polymer layer are covalently linkedto the lens core through a sulfonyl moiety such as, but not limited to,an alkylene sulfonyl moiety, a dialkylene sulfonyl moiety, an ethylenesulfonyl moiety, or a diethylene sulfonyl moiety. In further variations,the hydrophilic polymer layer is covalently attached to the core througha sulfonyl moiety and a thioether moiety, or an alkylene sulfonyl moietyand a thioether moiety, or a dialkylene sulfonyl moiety and a thioethermoiety, or an ethylene sulfonyl moiety and a thioether moiety, or adiethylene sulfonyl moiety and a thioether moiety.

In further variations, the hydrophilic polymer layer is covalentlyattached to the core through an ester moiety, or alkylene ester moiety,or an ethylene ester moiety, or a thioether moiety, or an ester moietyand a thioether moiety, or an alkylene ester moiety and a thioethermoiety, or an ethylene ester moiety and a thioether moiety.

In further embodiments, the linkage between the core lens and thehydrophilic layer is covalent, to the particular exclusion of any otherform of chemical bond or association. For example, a hydrogel layer asdescribed may be bound to the surface of a hydrophobic lens core by achemical bond that consists of a covalent bond.

D. MULTI-LAYER CONTACT LENS

In some embodiments, the coated contact lens contemplated herein is alayered lens with a hydrophilic polymer layer on a silicone-containinglayer. Some variations provide for a silicone-containing layer and afirst polyethylene glycol-containing layer, wherein the firstpolyethylene glycol-containing layer and the silicon-containing layerare covalently attached to one another, and the contact lens has alayered structural configuration. In an exemplary embodiment, thecontact lens does not comprise a second silicone-containing layer. Inother embodiments, the contact lens does not comprise a secondpolyethylene glycol-containing layer. In another embodiment, the contactlens does not comprise either a second silicone-containing layer or asecond polyethylene glycol-containing layer. In an exemplary embodiment,the contact lens comprises an anterior surface and a posterior surfacewherein the anterior surface is the first polyethylene glycol-containinglayer and the posterior surface is the silicone-containing layer. In anexemplary embodiment, the contact lens comprises an anterior surface anda posterior surface wherein the anterior surface is thesilicone-containing layer and the posterior surface is the firstpolyethylene glycol-containing layer.

In an exemplary embodiment, the layer which forms the anterior surfaceand the layer which forms the posterior surface of the contact lens areof substantially the same thickness. In other cases, the layers mayindependently have any suitable thickness, including the thicknessdescribed above for either the hydrogel layer or the core.

In another aspect, the invention provides a contact lens comprising asilicone-containing layer, a first polyethylene glycol-containing layerand a second polyethylene glycol-containing layer, wherein the firstpolyethylene glycol-containing layer and the silicone-containing layerare covalently attached to one another, and the second polyethyleneglycol-containing layer and the silicone-containing layer are covalentlyattached to one another, and the contact lens has a layered structuralconfiguration. In an exemplary embodiment, the contact lens does notcomprise a second silicone-containing layer. In an exemplary embodiment,the contact lens described does not comprise a third polyethyleneglycol-containing layer. In an exemplary embodiment, the contact lensdoes not comprise either a second silicon-containing layer or a thirdpolyethylene glycol-containing layer. In an exemplary embodiment, thecontact lens comprises an anterior surface and a posterior surfacewherein the anterior surface is the first polyethylene glycol-containinglayer and the posterior surface is the second polyethyleneglycol-containing layer. In an exemplary embodiment, the contact lensdescribed in this paragraph comprises an anterior surface and aposterior surface wherein the anterior surface is the first polyethyleneglycol-containing layer and the posterior surface is the secondpolyethylene glycol-containing layer and the first and secondpolyethylene glycol-containing layer are substantially identical to eachother. In other cases, the first polyethylene glycol-containing layerhas a composition, dimension, or other characteristic independent of thesecond polyethylene glycol-containing layer.

In an exemplary embodiment, for any of the contact lenses of theinvention, the first polyethylene glycol layer and thesilicone-containing layer are covalently attached through a sulfonylmoiety. In an exemplary embodiment, for any of the contact lenses of theinvention, the first polyethylene glycol layer and thesilicone-containing layer are covalently attached through an alkylenesulfonyl moiety. In an exemplary embodiment, for any of the contactlenses of the invention, the first polyethylene glycol layer and thesilicone-containing layer are covalently attached through a dialkylenesulfonyl moiety. In an exemplary embodiment, for any of the contactlenses of the invention, the first polyethylene glycol layer and thesilicone-containing layer are covalently attached through an ethylenesulfonyl moiety. In an exemplary embodiment, for any of the contactlenses of the invention, the first polyethylene glycol layer and thesilicone-containing layer are covalently attached through a diethylenesulfonyl moiety. In an exemplary embodiment, for any of the contactlenses of the invention, the first polyethylene glycol layer and thesilicone-containing layer are covalently attached through a thioethermoiety.

In an exemplary embodiment, for any of the contact lenses of theinvention, the first polyethylene glycol layer and thesilicone-containing layer are covalently attached through a sulfonylmoiety and a thioether moiety. In an exemplary embodiment, for any ofthe contact lenses of the invention, the first polyethylene glycol layerand the silicone-containing layer are covalently attached through analkylene sulfonyl moiety and a thioether moiety. In an exemplaryembodiment, for any of the contact lenses of the invention, the firstpolyethylene glycol layer and the silicone-containing layer arecovalently attached through a dialkylene sulfonyl moiety and a thioethermoiety. In an exemplary embodiment, for any of the contact lenses of theinvention, the first polyethylene glycol layer and thesilicon-containing layer are covalently attached through an ethylenesulfonyl moiety and a thioether moiety. In an exemplary embodiment, forany of the contact lenses of the invention, the first polyethyleneglycol layer and the silicone-containing layer are covalently attachedthrough a diethylene sulfonyl moiety and a thioether moiety.

In an exemplary embodiment, for any of the contact lenses of theinvention, the second polyethylene glycol layer and thesilicone-containing layer are covalently attached through a sulfonylmoiety. In an exemplary embodiment, for any of the contact lenses of theinvention, the second polyethylene glycol layer and thesilicone-containing layer are covalently attached through an alkylenesulfonyl moiety. In an exemplary embodiment, for any of the contactlenses of the invention, the second polyethylene glycol layer and thesilicone-containing layer are covalently attached through a dialkylenesulfonyl moiety. In an exemplary embodiment, for any of the contactlenses of the invention, the second polyethylene glycol layer and thesilicone-containing layer are covalently attached through an ethylenesulfonyl moiety. In an exemplary embodiment, for any of the contactlenses of the invention, the second polyethylene glycol layer and thesilicone-containing layer are covalently attached through a diethylenesulfonyl moiety. In an exemplary embodiment, for any of the contactlenses of the invention, the second polyethylene glycol layer and thesilicone-containing layer are covalently attached through a thioethermoiety.

In an exemplary embodiment, for any of the contact lenses of theinvention, the second polyethylene glycol layer and thesilicone-containing layer are covalently attached through a sulfonylmoiety and a thioether moiety. In an exemplary embodiment, for any ofthe contact lenses of the invention, the second polyethylene glycollayer and the silicone-containing layer are covalently attached throughan alkylene sulfonyl moiety and a thioether moiety. In an exemplaryembodiment, for any of the contact lenses of the invention, the secondpolyethylene glycol layer and the silicone-containing layer arecovalently attached through a dialkylene sulfonyl moiety and a thioethermoiety. In an exemplary embodiment, for any of the contact lenses of theinvention, the second polyethylene glycol layer and thesilicone-containing layer are covalently attached through an ethylenesulfonyl moiety and a thioether moiety. In an exemplary embodiment, forany of the contact lenses of the invention, the second polyethyleneglycol layer and the silicone-containing layer are covalently attachedthrough a diethylene sulfonyl moiety and a thioether moiety.

In an exemplary embodiment, for any of the contact lenses of theinvention, the first polyethylene glycol layer and thesilicone-containing layer are covalently attached through an estermoiety. In an exemplary embodiment, for any of the contact lenses of theinvention, the first polyethylene glycol layer and thesilicone-containing layer are covalently attached through an alkyleneester moiety. In an exemplary embodiment, for any of the contact lensesof the invention, the first polyethylene glycol layer and thesilicone-containing layer are covalently attached through an ethyleneester moiety. In an exemplary embodiment, for any of the contact lensesof the invention, the first polyethylene glycol layer and thesilicone-containing layer are covalently attached through a thioethermoiety.

In an exemplary embodiment, for any of the contact lenses of theinvention, the first polyethylene glycol layer and thesilicone-containing layer are covalently attached through an estermoiety and a thioether moiety. In an exemplary embodiment, for any ofthe contact lenses of the invention, the first polyethylene glycol layerand the silicone-containing layer are covalently attached through analkylene ester moiety and a thioether moiety. In an exemplaryembodiment, for any of the contact lenses of the invention, the firstpolyethylene glycol layer and the silicone-containing layer arecovalently attached through an ethylene ester moiety and a thioethermoiety.

In an exemplary embodiment, for any of the contact lenses of theinvention, the second polyethylene glycol layer and thesilicone-containing layer are covalently attached through an estermoiety and a thioether moiety. In an exemplary embodiment, for any ofthe contact lenses of the invention, the second polyethylene glycollayer and the silicone-containing layer are covalently attached throughan alkylene ester moiety and a thioether moiety. In an exemplaryembodiment, for any of the contact lenses of the invention, the secondpolyethylene glycol layer and the silicone-containing layer arecovalently attached through an ethylene ester moiety and a thioethermoiety.

E. CONTACT ANGLE

Advantageously, some of the contemplated coated contact lens provide fora hydrophilic polymer layer that has a population of hydrophilicpolymers that are cross-linked with each other and, moreover, are as awhole, covalently attached to a lens core or layer. As such, thehydrophilic polymer layer can improve the wettability of the corecontact lens.

As described in further detail below, the hydrophilicity or wettabilityof the hydrogel layer may be measured by a contact angle goniometer thatimplements a method known as a captive bubble contact angle test.Relatively high hydrophilicity is associated with a relatively lowadvancing contact angle.

In typical embodiments of the contact lenses according to the disclosedtechnology, when the lens is subjected to a bubble contact angle test,the lens shows an advancing contact in the range about 20° to about 50°.In more particular embodiments, the lens shows an advancing contact inthe range about 25° to about 35°.

FIGS. 6A-6C show aspects of a captive bubble test that is commonly usedin the contact lens industry as a surrogate measure of wettability orhydrophilicity of contact lenses, as provided by embodiments of thetechnology. FIG. 6A shows the setup 100 for a captive bubble test. Thesetup 100 includes a lens holding fixture 102 in communication with atest lens 104. An air bubble 106 is positioned at a surface of the testlens from a syringe pump 108.

FIG. 6B shows a schematic view of the contact angle as it occurs in anaqueous solution between the surface of a contact lens and an airbubble, as the air bubble is being inflated against or being withdrawnaway from the contact lens.

FIG. 6C provides a schematic series of angles created as a bubble isbeing inflated against the contact lens surface, and then withdrawn. Theleft side of the drawing depicts the “receding phase” of the test; theright side of the drawing depicts the “advancing phase of the test. Onthe left, after the bubble first makes contact at what will be thecentral contact point between the bubble and the contact lens, the areaof mutual contact expands, and the surrounding aqueous space recedesfrom the central contact point. Accordingly, this is termed the“receding phase”. On the right, as the bubble is being withdrawn, theaqueous solution advances toward the central point of contact betweenthe bubble and the contact lens. Accordingly, this is termed the“advancing phase” of the test. These profiles can be videographed duringthe test to capture the dynamics. In the recorded videos, software-basededge detection and angular separation techniques can be used to measurethe receding and advancing angles at the interface of the bubble andlens.

In both the advancing and receding portions of the test, a small anglereflects the relatively high affinity of the contact lens surface forwater, rather than air. Thus, there is an association between a smallcontact angle and hydrophilicity or wettability of the contact lenssurface. In contrast, a large contact angle reflects a relative lack ofaffinity of the contact lens surface with water. By means of this test,the hydrophilicity of contact lens embodiments of the technology may bequantified.

In an exemplary embodiment, the contact lens having a hydrophilicpolymer layer as described has an advancing contact angle of at least 20degrees, or at least 25 degrees, or at least 30 degrees, or at least 35degrees, or at least 40 degrees. In another embodiment, the advancingcontact angle is between about 20 degrees and about 40 degrees, orbetween about 20 degrees and about 35 degrees, or between about 20degrees and about 30 degrees, or between about 20 degrees and about 25degrees, or between about 25 degrees and about 40 degrees, or betweenabout 25 degrees and about 35 degrees, or between about 25 degrees andabout 30 degrees, or between about 30 degrees and about 40 degrees orbetween about 35 and about 40 degrees. In another variation, theadvancing contact angle is at least about 8 degrees, or at least about 9degrees, or at least about 10 degrees, or at least about 11 degrees, orat least about 12 degrees, or at least about 13 degrees. In an exemplaryembodiment, the advancing contact angle is between about 8 degrees andabout 20 degrees, or between about 8 degrees and about 17 degrees, orbetween about 8 degrees and about 14 degrees, between about 8 degreesand about 12 degrees, or between about 9 degrees and about 20 degrees,or between about 9 degrees and about 17 degrees, or between about 9degrees and about 14 degrees, between about 9 degrees and about 12degrees, or between about 10 degrees and about 20 degrees, or betweenabout 10 degrees and about 17 degrees, or between about 10 degrees andabout 14 degrees, between about 10 degrees and about 12 degrees, orbetween about 11 degrees and about 20 degrees, or between about 11degrees and about 17 degrees, or between about 11 degrees and about 14degrees.

F. METHODS OF MAKING A COATED CONTACT LENS OR MULTI-LAYERED CONTACT LENS

Another aspect of the invention provides for methods of making describedcoated and/or layered contact lenses.

In some embodiments, the method includes the steps of reacting a surfaceof a contact lens with a hydrophilic polymer solution. The hydrophilicpolymer solution may contain one or more subpopulations or species thatare adapted to react to form a coating on at least a portion of thecontact lens. In some cases, the hydrophilic polymer solution reacts toform a cross-linked coating on the contact lens. The coating may bepartially or substantially completely cross-linked.

As shown in FIG. 3A, the hydrophilic polymer solution may include afirst polymer species with a reactive group A and a second polymerspecies with a reactive group N. The hydrophilic polymer layer may beformed on the contact lens by reacting the reactive groups on the firstand second polymer species to form the cross-linked hydrophilic polymerlayer. As shown in FIG. 3B, the reactive groups A and N may form acovalent linkage 54 between the first and second polymer species tothereby cross-link the two species and result in a hydrophilic polymerlayer. In some cases, the reaction between the first and second reactivegroups on respective polymer species forms a hydrogel.

As described, any suitable reaction may be employed to form thehydrophilic polymer layer. These include (without limitation)nucleophilic conjugate reactions, Michael-type reactions (e.g. 1,4nucleophilic addition reactions), and/or click reactions. In some cases,the reactive groups A and N are an electron pair accepting moiety and anucleophilic moiety respectively.

Additionally, in some variations, the polymer species or subpopulationwith in the hydrophilic polymer layer may include PEG species. In somecases, a first PEG species reacts with a second PEG species to form thehydrophilic polymer layer. For example, the first PEG species mayinclude an electron pair acceptor adapted to react to a nucleophilicreactive moiety of a second PEG species to covalently link the PEGspecies.

Some embodiments provide for a covalent attachment between thehydrophilic polymer layer and the lens core or layer. For example, oneor more of the polymer subpopulation or species within the hydrophilicpolymer layer or solution may be adapted to react to the lens core toform a covalent attachment between the hydrophilic layer and the lenscore. In some cases, the method of hydrophilic polymer layer attachmentincludes the step of reacting at least one of the polymer species withreactive sites on the surface of the core to form covalent bonds betweenthe polymer species and the core surface.

Referring again to FIGS. 5A-5C, a first polymer species P1 may include areactive group A that is adapted to react to a reactive group N2 of thecore 60 surface. The reaction between the A and N2 groups results in acovalent linkage 61 between the first polymer species P1 and the core60. As shown, the reactive group A may also be adapted to react withanother reactive moiety N1 of a second polymer species P2 to form thehydrophilic polymer layer. As such, a first reaction between P1 and P2forms the hydrophilic polymer layer and a second reaction couples thehydrophilic polymer layer to the core.

In some cases, the same reactive group A on the first polymer species P1is capable of reacting to either the reactive moiety N1 or N2. In onevariation, a first portion of the reactive A groups react to the N1moiety and a second portion of the reactive groups react to the N2moiety. In some embodiments, the first and second portions of thereactive A groups are on the same molecule of a polymer species. Infurther variations, the first and second portions of the reactive Agroups are on different branch arms of the same polymer species. Thedual reactions between P1 and P2, and P1 and core may occur in the samereactive vessel and during the same reaction time (or overlapping insome portion of the reaction time).

As described, any suitable reaction may be employed to form thehydrophilic polymer layer and attach the hydrophilic polymer layer tothe lens core. These include (without limitation) nucleophilic conjugatereactions, Michael-type reactions (e.g. 1,4 nucleophilic additionreactions), and/or click reactions. For example, the plurality ofreactions may all be nucleophilic conjugate reactions. Alternatively,the plurality of reactions may be different types of reactions.

In some embodiments, the first and second reactions are nucleophilicconjugate reactions, more particularly, both are 1,4-nucleophilicaddition Michael-type reactions. By way of example, in some embodiments,the nucleophilic reactive moiety of the first macromer populationcomprises a thiol group and the electron pair accepting moiety of thesecond macromer population comprises a sulfone group.

In other embodiments of the method the first and second nucleophilicconjugate reactions may be described more broadly as a “Click” typereaction. Click reactions, as originally described by Karl Sharpless andothers, refer to modular assembly of macromolecules that are typified asoccurring in an aqueous environment, delivering high yield as a resultof being driven to completion by large thermodynamic force, and creatingsubstantially no byproducts, or byproducts that are non-toxic tobiological systems. The click reactions are advantageous for applicationtoward the manufacture of contact lenses because the lenses may bereacted in an aqueous solution, without toxic byproducts, rapidly, andto high yield.

Other examples of click type reactions that could be used to attachbranched polymers in our immersive dip coating process including (a)general thiol-ene click reactions in general, (b) [3+2] cycloadditions,including the Huisgen 1,2-dipolar cycloaddition, (c) Diels-Alderreaction, (d) [4+1] cycloadditions between isonitriles (isocyanides) andtetrazines, (e) nucleophilic substitution especially to small strainedrings like epoxy and aziridine compounds, (f) carbonyl-chemistry-likeformation of ureas, and (g) addition reactions to carbon-carbon doublebonds, such as involve dihydroxylation or the alkynes in the thiolynereaction.

In a particular embodiment, the method of making the described coatedlens includes the steps of reacting an outer surface of the contact lenswith a first PEG species of a hydrophilic polymer solution, wherein thefirst PEG species comprises an electron pair accepting moiety and afirst portion of the electron pair accepting moiety forms a covalentattachment to the outer surface of the contact lens through a firstnucleophilic conjugate reaction; and reacting the first PEG species ofthe hydrophilic polymer solution with a second PEG species of thehydrophilic polymer solution, the second PEG species comprising anucleophilic reactive moiety adapted to covalently link to a secondportion of the electron pair accepting moiety of the first PEG speciesin a second nucleophilic conjugate reaction to thereby at leastpartially cross-link the first and second PEG species, wherein a PEGhydrogel coating is formed and covalently attached to the outer surfaceof the contact lens by the first and second nucleophilic conjugatereactions.

In additionally embodiments, the method includes activating a surface ofthe lens core. Activating the surface may form a plurality of chemicallyreactive sites on the surface. The reactive sites may be, for example,nucleophilic sites for reaction with a hydrophilic polymer.

Referring to FIG. 7, a lens 160 without reactive sites is shown with aplurality of reactive sites 162 following an activation or modificationprocess. In some cases, a plasma process is used to activate the surfaceof a core lens. The activation process may include the step of exposingthe outer surface of the lens core to gas plasma. In some embodiments,the lens is transferred to a holding device, typically metal, and placedin a vacuum plasma chamber. The lens is plasma treated in an atmosphericplasma to form reactive sites on the surface. In some cases, anatmospheric plasma is applied to lens at 200 mTorr for about 3 minutesto thereby result in nucleophilic functional sites on the lens. In someembodiments, the lens are dehydrated prior to the plasma treatment.

In further variations, the contact lens surface may be activated throughplasma treatment, preferably in oxygen or nitrogen gas. For example, thecontemplated process may include activating a core material in anitrogen plasma.

In other embodiments, activation of the contact lens surface can alsooccur through exposure to increasing pH's, for example solution pH ofabove 11.

In further embodiments, activation can also occur by modifying themonomer mix to include groups that are reactive to the branchedhydrophilic coating polymers. Activation of the monomer mix can be adirect activation, or activation with a protected group that is cleaved,for example by light or changing pH. In other cases, plasmapolymerization of functional silanes including mercapto and aminosilanes may be used for activation. Additionally, plasma polymerizationof allyl alcohol and allyl amine can also be used for activation.

In some embodiments, the core activation or modification step results ina reactive group N2 (shown in FIG. 5B) that is capable of reacting withat least one of the polymer species of the hydrophilic polymer layer. Insome cases, at least one of the polymer species in the hydrophilicpolymer layer reacts with a portion of the plurality of reactive siteson the core outer surface to form a covalent attachment between thehydrophilic polymer layer and the core surface. In some cases, the lenscore is activated prior to the formation of the hydrophilic polymerlayer on the core surface.

In some embodiments, the process of making the coated lens includes thestep of reacting the activated core surface with a population offunctionalized hydrophilic polymers. For example, the hydrophilicpolymers may include a population of functionalized branched hydrophilicmacromers with a first subpopulation functionalized with a nucleophilicreactive moiety and a second subpopulation functionalized with anelectron pair accepting moiety. In further embodiments, the method mayinclude reacting the functional moieties of two macromer subpopulationswith each other in a first nucleophilic conjugate reaction to formcovalent linkages between the two macromer subpopulations, therebyforming a cross-linked polymer network.

The method may also include reacting the electron pair acceptingmoieties of second macromer subpopulation and the nucleophilic moietiesof the activated lens core surface in a second nucleophilic conjugatereaction to covalently attach the electron pair accepting moieties tothe lens core surface. The first and second nucleophilic conjugatereactions, when complete, yield a contact lens that has a lens core witha cross-linked hydrophilic hydrogel layer covalently attached thereto.

As described, the first and second nucleophilic conjugate reactions maybe of the same type with the reactions differing by having differentreactants. The two reactions may involve the same electron pairacceptor, such as the hydrophilic polymer species comprising an electronpair acceptor that can participate in a plurality of reactions. Theplurality of reactions may differ by having distinctnucleophilically-reactive parent molecules, in one case, a hydrophilicpolymer species with a nucleophilic moiety, and in the second case, asilicone-based polymer of the lens core with a nucleophilic moiety.

Referring to FIG. 8, a schematic diagram 200 of two exemplary conjugateaddition reactions 214, 216 and the principal reactants are shown. Theprincipal reactants can be understood as nucleophilic moieties 202 andelectron pair accepting moieties 204. In a first reaction, a reactanthaving nucleophilic functional moiety, such as PEG-thiol 206, reactswith a reactant having an electron pair accepting functional moiety 204,such as PEG-sulfone 204; the product of the reaction 214 is a linkedpair of PEG molecules, linked by way of a central thioether bond. As thereaction proceeds among the functionalized PEG molecules, the PEG takesthe form of a linked network, and inasmuch as a PEG network ishydrophilic, in an aqueous environment, the network takes the form of anintegrated hydrogel.

In a second reaction 216, a reactant 204 having an electron pairaccepting functional moiety, such as PEG-sulfone 204, reacts with anucleophilic site on the surface of the silicone-based lens core 210;the product of this second reaction 216 is a covalent bond between thePEG-sulfone and the lens core. As above, inasmuch as the individualmolecular that covalently link to the activated silicone-based core alsoare included as a constituent of a hydrogel structure, the hydrogelstructure, as a whole, becomes covalently linked lens core.

FIG. 9A-9D show more detailed and particular aspects of reactants andreactions, as depicted schematically in FIG. 8. FIG. 9A shows asilicone-based lens core being activated by a plasma treatment to yielda lens surface covered with a bed of activated nucleophilic sites. FIG.9B shows the structure of examples of reactants, including a PEGmolecule, a Michael-Type electron acceptor such as a vinyl sulfonemoiety, a nucleophile functional group such as a thiol, and the detailof the Michael type reaction itself.

FIGS. 9C-9D show a reaction process whereby two subpopulations ofbranched hydrophilic polymer species, a first subpopulation with anucleophile functionality (N) and a second subpopulation with anelectron pair accepting functionality (A) are in a reaction solutionthat bathes a nucleophilically activated (N) lens core. In the lowerportion of FIG. 9D, per the first reaction as depicted in FIG. 8,reaction individual members of the two subpopulations have begun to linktogether by way of their functional groups, to form a hydrogel network.And, per the second reaction as depicted in FIG. 8, electron pairaccepting moieties (A) of hydrophilic polymers engage in covalentlinking with the nucleophilic sites on the lens surface, therebycovalently attaching the hydrogel network to the lens surface.

FIGS. 10A-10B provide flow diagrams of two variations of processes formaking a contact lens with a covalently attached hydrogel membrane. FIG.10A shows a process that includes a plasma activation method. Suchplasma treatment may include exposure to any of an oxygen plasma or anitrogen plasma. FIG. 10B shows a process that includes a chemical or“wet” activation method.

As described in FIG. 10A, a contact lens 320 plasma treated 324 to forma plurality of reactive sites on the contact lens. This may beaccomplished by placing the lens into a vacuum plasma chamber. In someembodiments, the lens is transferred to a holding device, typicallymetal, and placed in a vacuum plasma chamber. The lenses are plasmatreated in an atmospheric plasma at 200 mTorr for about 3 minutes,thereby creating nucleophilic functional sites on the lens. Asdescribed, the lens may be in a dehydrated state prior to the plasmatreatment.

Referring still to FIG. 10A, after the lens core is activated, theactivated lens core is placed into a solution that includes coatingpolymer and/or coating polymer species or precursors 324. The coatingpolymer may be any of the described hydrophilic polymers describedincluding a hydrophilic polymer population including subpopulations offunctionalized branched PEG species. In some cases, the solution alsoincludes isopropyl alcohol and water. The solution may have a pH>7. Thesolution may be agitated to create a well-stirred bath and the lensesincubate in the solution for some period of time. In some cases, theincubation time is about 50 minutes.

Optionally, the coating process may include extraction steps to removean unwanted component from the coated lens. For example, where asilicone-based lens core is used for a base or substrate, unreactedsilicone molecules in the lens cores are extracted or diffused out ofthe lenses. Advantageously, the extraction process removes raw lens corematerial (e.g. raw silicone for a silicone-containing core) that mayleach out of the lens into the ocular region. As such, further steps ofthe process may include transferring the lens to a solution of isopropylalcohol and water for a period of time such as about 50 minutes 326 tocontinue extracting unreacted silicone molecules from the lens cores.Additionally, as a second rinse 328, the lens may be transferred to afresh solution of isopropyl alcohol and water for a period of time suchas about 50 minutes to further extract unreacted silicone molecules fromthe lens cores. In some variations, the lens may also be transferredinto a water bath 330 to equilibrate in water for a period of time (e.g.about 50 minutes).

Additionally, as shown in FIG. 10A, the lens may be transferred to apackaging container with a packaging solution 332. The lens may also beautoclaved 334. In some cases, the lens is autoclaved at about 250° F.for about 30 minutes.

FIG. 10B describes a wet-activation process for activating a lens coreand coating the activated core. The process may begin with a lens in ahydrated state 370. The next step may include activating the hydratedsurface lens core 372. This may be accomplished by a plasma or chemicaltreatment. For example, ozone may be used to activate the core surface.Once activated, the activated lens may be placed into a solutioncontaining the coating material 374. The solution may include ahydrophilic polymer solution as described and water. In some cases, thesolution is at a pH>7. The solution may be agitated to create awell-stirred bath and the lens incubates therein. In some cases, thelens incubates for about 50 minutes.

Next, the lens may be transferred to a water bath to equilibrate inwater 376. The equilibration step may also serve to wash excess polymerfrom the lens. The lens may be equilibrated in water for about 50minutes. The lens may be transferred to a packaging container withpackaging solution 378. Additionally, as another step, the lens may beautoclaved. In some cases, the lens is autoclaved at about 250° F. forabout 30 minutes. After the autoclave step, the resulting coated lens isready for use 382.

Advantageously, the methods described herein provide for acost-effective coating process that can be integrated with contact lensmanufacturing processes currently employed in the industry.

Some embodiments of the method may be understood as an immersive method,wherein activated lens cores are immersed in a reaction solution withina stirred vessel, the solution including hydrophilic macromer reactants,and the reaction vessel operated to achieve appropriate reactionconditions. The reaction vessel and aspects of the conditions, inbiochemical engineering terms, may be understood as occurring in acontinuously stirred reaction tank (CSTR). In typical embodiments, thereacting steps occur within a reaction solution that has an aqueoussolvent. Such the aqueous solvent may include any one or more of water,methanol, ethanol, or any suitable aqueous solvent that solubilizes PEG.

FIG. 11A provides a schematic view of a continuously stirred tankreactor (CSTR) 400 suitable for performing the reaction described. TheCSTR 400 includes an agitator 402 for stirring the reaction contentswithin the tank. A feeding line or conduit 404 allows input or inflow406 of reaction solutions including a hydrophilic polymer solutioncontaining at least one polymer species. As shown, first and secondpolymer species flow into the CSTR 400. In some cases, the first andsecond polymer species have different flow rates VP1 and VP2respectively. In other cases, the flow rates may be the same.

FIG. 11A shows a plurality of contact lenses 404 a and 404 b in the CSTR400. In some cases, the contact lenses may be held in a mesh holder withopenings or sufficient porosity to allow contact between the held lensesand the solution in the CSTR.

FIG. 11A also shows an output or outflow opening or conduit 408 forremoving fluid from the CSTR 400. In some cases, the removed fluid isspent reaction fluid. The flow rate of the removed fluid may be designedas V₀.

In some cases, T_(p) indicates the polymer residence time and T_(C)indicates the contact residence time in the CSTR 400. FIG. 11B shows therelationship between polymer coating particle size as a function of timein a CSTR 400 where T_(P) is 1-72 hours and T_(C) is 0.25-24 hours.

In some variations, within the reaction solution, the total hydrophilicmacromer concentration in the solution typically ranges between about0.01 (w/v) % and about 0.50 (w/v) %. In some embodiments, the first andsecond macromer subpopulations are present in the solution atsubstantially equivalent concentrations. However, in other embodiments,the concentration of the reactive moiety of the second macromersubpopulation (an electron pair acceptor) exceeds the concentration ofthe reactive moiety of first macromer subpopulation (a nucleophile).

Having an excess of electron pair reactive moieties with respect to thenucleophilic reactive moieties can be advantageous for the reactionsincluded herein for the purpose of forming embodiments ofhydrogel-coated contact lenses in that the electron pair acceptingmoieties of the hydrophilic polymer subpopulation so-functionalized canparticipate in two reactions. The polymer subpopulation functionalizedwith the electron pair acceptors participates (1) in covalent crosslinking with the subpopulation functionalized with nucleophiles and (2)covalent attachment to nucleophilic sites on the silicone-based corelens surface. In contrast, the polymer subpopulation functionalized witha nucleophilic moiety engages only in the single reaction wherein itengages the polymer subpopulation functionalized with the electron pairaccepting moiety.

The reactant concentration may also be appropriately expressed in termsof the relative concentrations of the reactive moieties of theparticipant macromers, rather than the concentrations of the macromersthemselves. This follows from the possible variations in the degree towhich the macromers are decorated with the function moieties thatactually participate in the reactions. Accordingly, in some reactionembodiments, the concentration of the reactive moiety of the secondmacromer subpopulation exceeds the concentration of the reactive moietyof the first macromer subpopulation by at least about 1%. In moreparticular embodiments, the concentration of the reactive moiety of thesecond macromer subpopulation exceeds the concentration of the reactivemoiety of the first macromer subpopulation by an amount that rangesbetween about 1% and about 30%. And in still more particularembodiments, the concentration of the reactive moiety of the secondmacromer subpopulation exceeds the concentration of the reactive moietyof the first macromer subpopulation by an amount that ranges betweenabout 5% and about 20%.

Returning now to aspects of the reaction conditions, in someembodiments, the reacting steps are performed for a duration of betweenabout 5 minutes and about 24 hours. In particular embodiments, thereacting steps are performed for a duration of between about 0.5 hourand about 2 hrs. In some embodiments, the reacting steps are performedat a temperature at a range between about 15° C. and about 100° C. Inmore particular embodiments, the reacting steps are performed at atemperature at a range between about 20° C. and about 40° C. In someembodiments, the reacting steps are performed at a pH between about 7and about 11.

In some embodiments, the activated lens material is incubated in adilute reaction solution containing 4-arm branched, 10 kDa PEG endfunctionalized with thiol groups, and 8-arm branched, 10 kDa PEG endfunctionalized with vinyl sulfone groups. The dilute solution containsbetween 0.01 and 0.5% total polymer, with a 10% excess of vinyl sulfonegroups. The reaction can be performed in aqueous conditions, methanol,ethanol, or other solvents in which PEG is soluble. The reaction can beperformed at a range of temperatures between about 15 degrees C. andabout 100 degrees C. The reaction can be performed from between about 5minutes and about 24 hours. The reaction can be performed at basic pH's,preferably in the range of 7-11.

As polymer reaction proceeds in the dilute solution, hydrogels (e.g.cross-linked hydrophilic polymer particles) are formed as branchedpolymers react with each other. Reaction progress can be monitored usingdynamic light scattering techniques to measure hydrogel particle sizeand/or macromer aggregation level as the hydrogel network is forming.Temperature, pH, convection speed, and concentration will influencereaction rate and hydrogel particle size and formation rate. Hydrogelparticles that are smaller than visible light will not cause opticaldistortions in the contact lens. Layer thickness can be regulated bymonitoring hydrogel formation during the course of reaction.

In some variations, polyethylene glycol is the hydrophilic polymer.However, other multifunctional natural and synthetic hydrophilicpolymers can also be used, for example poly(vinyl alcohol),poly(vinylpyrrolidinone), Poly(N-isopropylacrylamide) (PNIPAM) andPolyacrylamide (PAM), Poly(2-oxazoline) and Polyethylenimine (PEI),Poly(acrylic acid), Polymethacrylate and Other Acrylic Polymers,Polyelectrolytes, hyaluronic acid, chitosan, dextran.

In other embodiments, the methods include the step of forming across-linked hydrophilic polymer layer on a lens surface that iscovalently attached to the contact lens. Covalent linkages between thebranched hydrophilic polymers may occur due to Michael type nucleophilicconjugate addition reaction between vinyl sulfone and thiol and covalentlinkages between the hydrophilic polymer and the lens surface occur dueto conjugate addition reaction between vinyl sulfone and nucleophilesgenerated during the activation step. In some cases, reactivity ofnucleophiles will increase with rising pH as molecules are increasinglydeprotonated.

In further variations, any general Michael type reaction betweenenolates and conjugated carbonyls can also be used. For example,acrylate, methacrylate, or maleimide can be substituted for vinylsulfone. Other examples include the Gilman reagent as an effectivenucleophile for addition to conjugated carbonyls. The stork enaminereaction can be performed using enamines and conjugated carbonyls.

Additional covalent reaction mechanisms include hydroxylamine reactionwith electrophiles such as aldehyde or ketone to produce oxime linkages.

Additional covalent reaction mechanisms include reaction ofN-Hydroxysuccinimidyl esters with amines.

Additional covalent reaction mechanisms include isocyanates reactionwith nucleophiles including alcohols and amines to form urethanelinkages.

An additional embodiment provides for a method of forming a contact lensthat includes casting of lenses in disposable soft molds. In someembodiments, a lens is coated in agar. This may be done by encapsulatingthe lens in a liquid agar solution. The agar is cooled and allowed toharden. After hardening, the encapsulated lens is removed from the agar,yielding an agar mold that includes a top piece, making the concave sideof the lens, and a bottom piece matching the convex side of the lens.The mold is taken apart, a first drop of liquid hydrogel solution isadded to the bottom half of the mold, followed by an activated lenscore, followed by another drop of liquid hydrogel solution, followed thetop half of the lens. The mold is then incubated until the hydrogelsolidifies, then the contact lens is removed from the mold, yielding alens with attached hydrophilic layers.

In some embodiments, a soft molding process employing agar is used. Forexample, Delrin plates may be machined with cavities (e.g. 12 cavities).To produce molds, agar may be melted and a small volume of liquid agaradded to a mold cavity, followed by a lens, and then additional liquidagar to cover the lens. The mold may be refrigerated to solidify theagar. In some cases, the mold is refrigerated for about 20 minutes inthe refrigerator to solidify the agar.

In further embodiments, a punch of the same diameter as the lens is usedto punch around the lens. A small vacuum pick-up tool can then be usedto remove the top of the mold, then a second vacuum pick-up tool can beused to remove the lens from the mold, and the top of the mold replaced.

This process can yield trays of soft disposable molds with a cavitymatching the lenses to be coated (the lenses used to make the molds maybe the same type as the ones to be coated, but not the actually lensesthat were ultimately coated).

To produce coated lenses, lens cores can be activated using one of themethods described above. The top of the agar lens mold may then beremoved and hydrogel precursor solution (e.g. 10 μL) added to the bottomof the mold, followed by the lens core, followed by more of hydrogelprecursor solution (e.g. 10 μL), followed by the lid of the mold.Forceps may be used to push the top of the mold down and remove anybubbles.

The tray of lenses can then be incubated. In some cases, the tray oflenses is incubated for 1 hour at 37° C. in order to polymerize thehydrogel. Following polymerization, the lenses may be removed from themolds and stored in PBS containing azide to prevent contamination.

To observe layer thickness, a small amount of fluorescein-maleimide maybe added to the hydrogel layer on a coated lens. Thefluorescein-maleimide reacts covalently with the hydrogel and enablesthe layer to be visualized using fluorescence microscopy.

In some cases, the coated lenses can be cut into 500 micron thicksections by striking 2 microtome blades held in parallel to cut the lensand leave a thin section between the blades. The lens cross section canbe visualized using a fluorescent microscope (this is for a lens onlyfunctionalized with hydrogel on one side, the uncoated side serves as aninternal control). In some cases, the average layer thickness wasestimated to be about 25 microns based on this technique.

Additionally, the soft agar molds may be used to coated siliconehydrogel core lenses as well as coated pure silicone cores. Lenses canalso be evaluated with the contact angle measurement technique describedor any other suitable techniques.

In another embodiment, a PEG containing layer can be attached to asilicone containing lens layer using cast molding techniques. First, thesilicone containing layer is modified to ensure surface groups arepresent that will react covalently with the PEG macromers. Second, moldsare prepared that contain a top part and a bottom part in the same orsimilar shape as the silicone containing layer. The silicone containinglayer is placed into the mold along with the liquid macromer PEGsolution and the mold halves are placed together. The PEG can curethermally for approximately 1 hour and the mold is taken apart.

The PEG containing layer can also be attached to the silicone containinglayer using a dip coating method. First, the silicone containing layeris modified to ensure surface groups are present that will reactcovalently with the PEG macromers. For example, surface groups can begenerated in a plasma treatment step, or by incubating in a basicsolution, or by including reactive groups in the monomer mix. Next, adip coating solution is prepared that consists of a dilute solution ofreactive, branched, hydrophilic polymers. The activated lens is placedin the dip coating solution and incubated for 1-24 hours. Followingincubation, the lens is rinsed thoroughly and then autoclaved in anexcess volume of buffer solution prior to measuring captive bubblecontact angles.

In alternative method, the hydrophilic polymer layer can be covalentlyattached to the silicone containing layer using another dip coatingmethod. First, the silicone containing layer can be modified to createsurface chemical moieties that are covalently reactive to thehydrophilic macromers. For example, surface groups can be generated in aplasma treatment step, or by incubating in a basic solution, or byincluding reactive groups in the monomer mix. Next, a dip coatingsolution can be prepared that consists of a dilute solution of reactive,branched, hydrophilic polymers. For example, the dilute solution canconsist of a branched poly(ethylene glycol) end functionalized withvinyl sulfone and thiol in a solution containing 0.2M triethanolamine.The activated lens is placed in the dip coating solution and incubatedfor 1-24 hours at a temperature between about 20° C. and about 60° C.Following incubation, the lens is rinsed thoroughly and then autoclavedin an excess volume of phosphate buffered saline.

In an exemplary embodiment, the invention provides a method of making acontact lens described herein. The method comprises contacting anactivated lens and a dip coating solution, thereby making a contactlens. In an exemplary embodiment, the method further comprisesactivating a lens, thereby creating an activated lens. A lens can beactivated through a method known to one of skill in the art or a methoddescribed herein, such as plasma treatment or incubation in a basicsolution, or by including reactive groups in the monomer mix. In anexemplary embodiment, the contacting takes place for between 1-24 hours,or from 1-12 hours, or from 12-24 hours, or from 6-18 hours. In anexemplary embodiment, the method further comprises rising the lens afterthe contacting step. In an exemplary embodiment, the method furthercomprises autoclaving the lens after the contacting step. In anexemplary embodiment, the method further comprises autoclaving the lensafter the rinsing step.

In another embodiment, an alternative method of forming a contact lensincludes a spray coating approach wherein a reactive ultrasonic spraycoating is used to coat substrates with a thin, adhered layer ofcross-linked hydrogel. A two-component hydrogel, comprising branched PEGend-capped with vinyl sulfone, and branched PEG end-capped with thiol,was used to produce the cross-linked thin films. The two components aresimultaneously dripped onto an ultrasonic spray nozzle where they arecombined and atomized into small droplets, which then are accelerated tothe substrate in an air sheath. The rate of reaction is adjusted toensure that reaction is fast enough that a solid structure forms on thesurface, but slow enough that the components do not instantly polymerizeupon mixing at the nozzle.

An alternative spray method, considered appropriate for scaledmanufacturing, is ultrasonic spray coating, a technique that enablesprecise, thin film coatings. It has been employed previously for stentsand in the microelectronics industry, and is currently used in severalhigh volume manufacturing lines. A state of the art Sonotek instrumentwas used to form coated contact lens prototypes. This technology enables3D printing, thus potentially providing a platform for constructingcomplicated lens structures with integrated sensors or electronics.

The Sonotek instrument has an ultrasonically driven spray nozzle withtwo feed lines that deposit solution onto the tip. A two-componenthydrogel system involves dissolving the PEG vinyl sulfone component inmethanol containing triethanolamine (TEOA; acting as an organic base)and the PEG thiol component in pure methanol. The two solutions aredelivered to the nozzle tip at a rate of 5 microliters per minute andthe concentration of each PEG component is adjusted such that equalvolumes of each component mix to achieve a 10% molar excess of vinylsulfone groups. When the solutions are deposited on the ultrasonic tip,they mix and are atomized into droplets that are approximately 20microns in diameter. A pressured air sheath then accelerates thedroplets onto the surface to be coated. By including FITC-malelimide inthe PEG vinyl sulfone component, mixing and crosslinking that result infilm deposition can be films. A concentration of TEOA and identifiedthat at a molar ratio of TEOA:SH of 6:1 could deposit a uniformcrosslinked hydrogel on a variety of substrates, including pure siliconeand silicone hydrogel core lenses. An alternative aqueous spray coatingmethod was also tested and was shown to be feasible, however for thecontact lens substrates, the methanol process advantageously produces ahighly uniform film of ˜5 microns. The contact angle measurements oncoated lenses demonstrated the integrity of the deposited film.

FIGS. 12A and 12B depict alternative embodiments of methods of thetechnology that are directed toward making lenses with a covalentlyattached bilateral hydrogel layer, in which the hydrogel layer sidesdiffer in composition or depth. In some instances, it may beadvantageous to produce a contact lens that is asymmetric (convex sidevs. concave side) with regard to the thickness or composition of thehydrogel coating that is associated with the two surfaces, respectively.For example, it may be advantageous to form a hydrogel layer on theconcave (or posterior) lens surface that is thicker than the layer onthe convex (or anterior) lens surface, in order to hold a greater volumeof aqueous tears against the cornea and prevent symptoms of dryness.

FIG. 12A shows a method to produce a lens with a thicker hydrophiliclayer on the concave surface 503 in which a lens core 500 containing aUV blocking agent is dipped into a non-mixed solution 502 of coatingpolymer, and then exposed to UV light 504. UV light accelerates thereaction between polymers as well as the reaction between polymer andsurface. The light strikes the lens on a vector that is perpendicular tothe lens surface, directly onto the concave side 503 and through theconvex side 501. Due to the UV blocking agent present in the lens, theconcave side 503 is exposed to a higher dose of UV light, while theconvex side 501 receives a relatively lower dose. This asymmetric UVdosing creates layers of varying thickness. To achieve completeindependent variation in layer thickness control, light dosage ofvarying intensity can also be used to shine from each side.

FIG. 12B shows an alternative method for producing a thicker hydrogellayer on the concave surface 503 of the lens 500. As shown, the convexsurface 501 of the lens 500 is held in a vacuum chuck 506 while exposingthe concave surface 503 to the coating polymer 502. The vacuum suctionpulls the aqueous solvent through the lens 500 while concentratingcoating polymer at the lens interface at the concave surface 503. Afterachieving a desired layer thickness, the lens 500 is removed from thechuck 506. In some variations, the lens 500 is then placed into awell-mixed bath of coating polymer, to continue building the hydrogellayer on both sides of the lens.

G. EXAMPLES

The invention is further illustrated by the Examples that follow. TheExamples are not intended to define or limit the scope of the invention.

Example 1 Functionalization of Silicone Hydrogel Lenses

Silicone hydrogel lenses were stored in purified water prior tofunctionalization. A solution of 10% by volume divinyl sulfone in 0.5Msodium bicarbonate (pH 11) were prepared. Lenses were added to thesolution at a ratio of 6 lenses per 10 mL of solution and mixedvigorously on a shake plate for 60 minutes. The lenses were removed,washed in a strainer to remove any excess reaction solution, and addedto a container of purified water at a ratio of 1 lens per 20 mL ofwater. They were mixed vigorously on a shake plate for 60 minutes. Thewashing procedure was repeated twice more for a total of 3 washes. Next,the lenses were stored in triethanolamine (TEOA) for at least 20 minutesand up to 6 hours prior to attaching the hydrogel layer.

Example 2 Functionalization of Silicone Lenses

Silicone lenses were stored dry prior to functionalization. Lenses wereadded to a solution of 10% hydrochloric acid and 2% hydrogen peroxide ata ratio of 6 lenses per 10 mL. The lenses were mixed vigorously for 5minutes and then removed, washed in a plastic strainer to remove anyexcess reaction solution, and then added to a container of purifiedwater a ratio of 1 lens per 20 mL of water. They were mixed vigorouslyfor 5 minutes. Next the lenses were added to a solution of 95% ethanol,3% water, 1% glacial acetic acid, and 1%3-mercaptopropyltrimethoxysilane and mixed vigorously for 60 minutes.The lenses were rinsed in a strainer with pure ethanol and added to acontainer of pure ethanol at a ratio of 1 lens per 20 mL of ethanol. Thelenses were mixed vigorously for 60 minutes. This washing procedure wasrepeated once more. Finally the lenses were removed from the rinsesolution and allowed to dry. They were stored at 4° C. Prior toattaching hydrogel to the lenses, they were immersed in a solution of150 mM dithiothreitol for 30 minutes and then rinsed in DI water.Following this step, hydrogel must be attached within 15 minutes.

Example 3 Plasma Functionalization of Silicone Containing Layers

Silicone containing layers (silicone or silicone hydrogel) were placedin a vacuum chamber for 2 hours to ensure all moisture was removed.After drying, lenses were inserted into a plasma chamber. Pressure wasreduced to 375 milliTorr with continuous flow of nitrogen gas at 10standard cubic centimeters per minute. The chamber was allowed tostabilize for 30 seconds before initiating plasma at 100 W for 3minutes. The chamber was then vented to atmosphere and lenses removed.Lenses were then used within 1 hour.

Example 4 Preparation of Molds for Adding Bulk Layers to Contact Lenses

Molds were prepared using silicone hydrogel lenses and agar. 5 grams ofAgar were dissolved in 333 mL of water and the solution was heated on atemperature controlled stirred plate until it reaches 88° C. A delrinplate containing small cavities (1″ in diameter and 0.5″ deep) was usedto contain each individual mold. Liquid agar is pipetted to fill a moldcavity half full. A contact lens was then placed, convex side down, ontop of the molten agar and additional agar was added on top tocompletely encase each lens in agar. Each plate contained 12 moldcavities and upon forming all 12, the plate was placed at 4° C. for 10minutes until it is completely solidified. Once solid, a small brasspunch of the same diameter as the contact lens (14 mm) was used to puncha hole in the agar around each lens. A hand held vacuum suction cup wasused to pull the top of the agar mold off, tweezers were used to removethe silicone hydrogel lens, and then the top of the mold was replaced.This is repeated for each mold. Molds were then ready to be used forhydrogel attachment.

Example 5 Preparation of Poly(Ethylene Glycol) Hydrogel MacromerSolutions

The PEG hydrogel consists of two components. The first is 8-arm, 10 kDapoly(ethylene glycol) (PEG) end functionalized with vinyl sulfone(PEG-VS). The second is 4-arm, 10 kDa PEG end functionalized with thiolgroups (PEG-SH). The PEG-VS was dissolved to 10% w/v in triethanolaminebuffer (TEOA) at pH 8.0 and then filter sterilized in a 0.45 micron PVDFfilter. The PEG-SH was dissolved to 10% w/v in distilled water and thenfilter sterilized in a 0.45 micron PVDF filter.

Example 6 Fabrication of a PEG Hydrogel

To form a PEG hydrogel, the macromer solutions of Example 5 were mixedtogether. To achieve varying polymer concentrations, a diluting volumeof TEOA was added to the PEG-VS solution prior to mixing. The componentswere combined together with a 10% molar excess of thiol groups. Thetable below lists quantities used to fabricate various weight percentagePEG hydrogels. For example, to form a 5% PEG hydrogel: 96 μL of TEOA,was added to 30 μL of PEG-VS in an eppendorf tube. Finally, 66 mL ofPEG-SH was added to the tube and it is mixed using a vortex for 3seconds to ensure complete mixing. The PEG hydrogel was then incubatedat 37° C. for 1 hour to ensure complete polymerization.

Volume (μL) Hydrogel TEOA PEG-VS PEG-SH Total 4% 115.2 24.0 52.8 192.05% 96.0 30.0 66.0 192.0 6% 76.8 36.0 79.2 192.0 7% 57.6 42.0 92.4 192.08% 38.4 48.0 105.6 192.0 9% 19.2 54.0 118.8 192.0 10% 0.0 60.0 132.0192.0

Example 7 Determining a Non-Swelling PEG Hydrogel Formulation

PEG hydrogel macromer solutions of Example 6 were pipetted between twohydrophobic glass slides separated by a 1 mm spacer and allowed toincubate at 37° C. for 1 hour. To determine swelling ratio, the PEGhydrogel was weighed immediately following polymerization and thenimmersed in distilled water for 24 hours. The swollen PEG hydrogel wasweighed again to determine the amount of water absorbed into the polymernetwork to determine the mass fold increase. As seen below, the masschange for all PEG hydrogel formulations was small and the PEG hydrogelformulation of 5% did not undergo any swelling following polymerization.

Example 8 Fabricating a Contact Lens with a Bulk Layer of PEG Hydrogelon the Concave Side

To produce a contact lens with a bulk layer of PEG hydrogel, the moldsof Example 3 were prepared using sacrificial lenses identical to thosereceiving a bulk layer of PEG hydrogel. A solution of 50% by volumeTEOA, 34.4% PEG-SH, and 15.6% PEG-VS were prepared by mixing in aneppendorf tube and vortexing. The top of the agar mold was removed usinga small hand held vacuum suction device and the functionalized lens (ofeither Example 1 or Example 2 or Example 3) were placed into the mold.20 μL of the mixed PEG solution was placed onto the concave side of thelens, and the top of the agar mold was replaced on top. Air bubbles wereremoved by gently tapping on the top of the mold until all air wasremoved from the mold. The mold was placed in an incubator at 37° C. for1 hour. The lenses were then removed, visually inspected, and placed inpurified water for storage.

Example 9 Fabricating a Contact Lens with a Bulk Layer of PEG Hydrogelon the Convex Side

To produce a contact lens with a bulk layer of PEG hydrogel, the moldsof Example 3 were prepared using sacrificial lenses identical to thosereceiving a bulk layer of PEG hydrogel. A solution of 50% by volumeTEOA, 34.4% PEG-SH, and 15.6% PEG-VS were prepared by mixing in aneppendorf tube and vortexing. The top of the agar mold were removedusing a small hand held vacuum suction device and 20 μL of the mixed PEGsolution was placed into the bottom of the mold. The functionalizedlenses (of either Example 1 or Example 2 or Example 3) were placed intothe mold and the top of the agar mold was replaced on top. Air bubbleswere removed by gently tapping on the top of the mold until all air wasremoved from the mold. The mold was placed in an incubator at 37° C. for1 hour. The lenses are then removed, visually inspected, and placed inpurified water for storage.

Example 10 Fabricating a Contact Lens with a Bulk Layer of Hydrogel onboth Concave and Convex Sides (Encased)

To produce a contact lens encased in a bulk layer of PEG hydrogel, themolds of Example 4 were prepared using sacrificial lenses identical tothose receiving a bulk layer of PEG hydrogel. A solution of 50% byvolume TEOA, 34.4% PEG-SH, and 15.6% PEG-VS was prepared by mixing in aneppendorf tube and vortexing. The top of the agar mold was removed usinga small hand held vacuum suction device and 20 μL of the mixed PEGsolution is placed into the bottom of the mold. The functionalized lens(of either Example 1 or Example 2 or Example 3) were placed into themold and 20 μL of the mixed PEG solution was placed onto the concaveside of the lens and then the top of the agar mold was placed on top.Air bubbles were removed by gently tapping on the top of the mold untilall air was removed from the mold. The mold was placed in an incubatorat 37° C. for 1 hour. The lenses were then removed, visually inspected,and placed in purified water for storage.

Example 11 Oaysys Lenses Encapsulated in PEG Hydrogel

Contact lenses (Acuvue Oaysys, lotrafilcon A) were functionalizedaccording to Example 1. Agar molds were prepared according to Example 4.Lenses were encapsulated according to Example 10.

Example 12 Oaysys Lenses with a Bulk Layer of PEG Hydrogel

Contact lenses (Acuvue Oaysys, lotrifilcon A) were functionalizedaccording to Example 1. Agar molds were prepared according to Example 4.A bulk layer was added according to Example 8.

Example 13 PureVision Lenses Encapsulated in PEG Hydrogel

Contact lenses (PureVision, balafilcon A) were functionalized accordingto Example 1. Agar molds were prepared according to Example 4. Lenseswere encapsulated according to Example 10.

Example 14 PureVision Lenses with a Bulk Layer of PEG Hydrogel

Contact lenses (PureVision, balafilcon A) were functionalized accordingto Example 1. Agar molds were prepared according to Example 4. A bulklayer was added according to Example 8.

Example 15 Silicone Lenses Encapsulated in a Bulk Layer of PEG Hydrogel

Silicone lenses (NuSil, Med 6755) were functionalized according toExample 2. Agar molds were prepared according to Example 4. Lenses wereencapsulated according to Example 10.

Example 16 Silicone Lenses with a Bulk Layer of PEG Hydrogel on theConcave Side

Silicone lenses (NuSil, Med 6755) were functionalized according toExample 2. Agar molds were prepared according to Example 4. A bulk layerwas added according to Example 8.

Example 17 Silicone Lenses with a Bulk Layer of PEG Hydrogel on theConvex Side

Silicone lenses (NuSil, Med 6755) were functionalized according toExample 2. Agar molds were prepared according to Example 4. A bulk layerwas added according to Example 9.

Example 18 Contact Angle Measurement

To measure lens contact angles, the captive bubble technique was used.First, the lens was spun in a vortex in distilled water to removesurface contaminants. The lens was then submerged in distilled water andsuspended atop a plate that has a hole through which the convex surfaceof the lens protrudes downward. An 11/16″ diameter stainless steel ballwas placed atop the lens to keep it in place when the bubble wasapplied. Next, the curved tip of a 16 gauge blunt needle was placed justbelow the surface of the center of the lens. A bubble was then advanceduntil it makes contact with the lens, at which point the bubble wasretracted until it breaks free from either the lens or the needle. Ahigh-definition video camera records the entire procedure, after whichan image was saved from the frame immediately preceding the moment thebubble detaches from either the lens or the needle. From this image, theangles between the lens and the bubble on both sides of the bubble werecalculated in MATLAB and saved as the contact angles for that lens.

Example 19 Contact Angle Measurement of Oasys Lenses with Bulk Layers ofPEG Hydrogel

The contact angle of lenses of Example 11 were measured according toExample 18.

Lens with bulk layers of PEG hydrogel Contact Angle* Lens 1 12.3 Lens 214.6 Lens 3 10.7 Average 12.5 *Contact angle is the average of 3 tests

Example 20 Preparation of Photo-Polymerizable Poly(Ethylene Glycol)Hydrogel Macromer Solutions

The hydrogel consists of two components. The first is 8-arm, 10 kDapoly(ethylene glycol) (PEG) end functionalized with acrylate (PEG-Ac).The second is 4-arm, 10 kDa PEG end functionalized with thiol groups(PEG-SH). The PEG-Ac is dissolved to 10% w/v in triethanolamine buffer(TEOA) at pH 8.0 and then filter sterilized in a 0.45 micron PVDFfilter. The PEG-SH is dissolved to 10% w/v in distilled water and thenfilter sterilized in a 0.45 micron PVDF filter.

Example 21 Fabrication of a Photo-Polymerizable PEG Hydrogel

To form a hydrogel, the macromer solutions of Example 20 are mixedtogether. To achieve varying polymer concentrations, a diluting volumeof TEOA is added to the PEG-Ac solution prior to mixing. The componentsare combined together with a 10% molar excess of thiol groups. The tablebelow lists quantities used to fabricate various weight percentagehydrogels. For example, to form a 5% PEG hydrogel: 96 μL of TEOA, isadded to 30 μL of PEG-Ac in an eppendorf tube. Finally, 66 mL of PEG-SHis added to the tube and it is mixed using a vortex for 3 seconds toensure complete mixing. The solution is then exposed to UV light (365nm, 5 mW/cm2, 10 min) to polymerize the mixture.

Volume (μL) Hydrogel TEOA PEG-Ac PEG-SH Total 4% 115.2 24.0 52.8 192.05% 96.0 30.0 66.0 192.0 6% 76.8 36.0 79.2 192.0 7% 57.6 42.0 92.4 192.08% 38.4 48.0 105.6 192.0 9% 19.2 54.0 118.8 192.0 10% 0.0 60.0 132.0192.0

Example 22 Layer by Layer Reactive Spin Coating

The macromer solutions of Example 20 are prepared. Lenses of Example 1or 2 or Example 3 are fixed to a spin coater chuck. The lenses arerotated at speeds ranging from 500-5000 rpms. While revolving, the lensis continuously exposed to UV light (365 nm, 5 mW/cm2), while drops ofmacromer solution are alternately added to the lenses as follows: 10 μLof PEG-Ac followed by 10 μL of PEG-SH, etc. This is repeated formultiple cycles, ranging from 10-1000.

Example 23 PEG Dipping Solution for Enzyme Mediated Redox ChainInitiation

The PEG dipping solution consists of a mixture of glucose oxidase (GOX),Fe+2, and polyethylene glycol diacrylate (PEGDA) (MW from 2,000Da-10,000 Da). For example, a dipping solution may contain 3.1×10-6 MGOX, 2.5×10-4 M iron (II) sulfate, 10% PEGDA 5,000 Da.

Example 24 Contact Lens Encapsulated in PEG Hydrogel Via InterfacialEnzyme Mediated Redox Chain Initiation

The glucose loaded lenses of Example 18 are dipped into the solution ofExample 19 until the hydrogel layer grows to the desired thickness. Thetime to achieve a layer thickness of 10-100 microns ranges from 2seconds-10 minutes.

Example 25 Captive Bubble Contact Angle Measurement

A macro lens of 10× magnification was affixed to the camera detailed inExample 17, Contact Angle Measurement. The macro lens enables close-upmovies of the bubble/contact lens interface. A syringe pump (New EraSyringe Pump 750) was added to the testing fixture to enable continuousand repeatable bubble control. The pump was programmed using SyringePump Pro programming software. A new test fixture chamber wasconstructed of black acrylonitrile butadiene styrene (abs) to facilitatethe use of a thin, clear, glass viewing plate and a semi-opaquebackground screen. The tested lens were held between two plates andsubmerged in PBS. An air bubble was extended 2 mm from a straight 16gage blunt needle until it made contact with the lens. A high-definitionweb camera recorded the lens+bubble interface while 3 μl of air wasinfused and then withdrawn at a rate of 7.2 μl/min from themicro-syringe (Precision Sampling corp, series A-2, 25 ul). The contactangle of lenses described herein were measured using Example 25 and aredetailed in FIGS. 13A-13T. The contact angles were measured usingspecially developed MatLab Code which is detailed in FIGS. 14A-14J.

Example 26 PEG Concentration Dependence

To determine the effect of PEG concentration on polymerization rate forthe hydrogel, the macromer solutions of Example 4 were combined atdecreasing concentrations and checked at set time intervals untilsolidification. PEG-VS and PEG-SH were combined in the below quantitieswith the specified quantity of 0.2M TEOA in 1.5 ml eppendorf tubes toform the noted concentrations. Each solution was vortexed and thenpippeted onto a glass slide. The PEG solution was pippeted at 5, 10, or30 second intervals (increasing time interval for lower concentrations)until filaments formed, indicating that the gel had polymerized. Thetime-until-polymerization was recorded.

PEG Concentration 1% 2% 3% 4% 6% 8% 10% Volume PEG-VS 10.6 10.6 16.021.3 31.9 42.6 53.2 (μL) PEG-SH 19.4 19.4 29.0 38.7 58.1 77.4 96.8 TEOA270 120 105 90 60 30 0 Total Volume 300 150 150 150 150 150 150Polymerization 8820 680 406 250 150 103 83 Time (Sec)

Example 27 PEG pH Dependence

To determine the polymerization rate of the hydrogel as a function ofpH, the macromer solutions of Example 4 were combined with 0.2M TEOA atincreasing pH levels. 20% PEG-VS and 10% PEG-SH were combined in thebelow quantities with TEOA at the specified pH in 1.5 ml eppendorftubes. The TEOA buffer was prepared at the noted concentrations byadjusting pH with NaOH or HCl as required. A 4% hydrogel solution wasmade. Each solution was vortexed and then pippeted onto a glass slide.The PEG solution was pippeted at 5, 10, or second intervals (increasingtime interval for lower pH) until filaments formed, indicating that thegel had polymerized. The time-until-polymerization was recorded.

Example 28 Lenses Dip Coated to Obtain a Bulk Layer of PEG

Lenses were functionalized using nitrogen gas in a plasma chamber(Plasma Etch PE-50) at settings: 375 mTorr, 3 min, 100% RF power.Pressure was reduced to 375 milliTorr with continuous flow of nitrogengas at 10-20 standard cubic centimeters per minute. The chamber wasallowed to stabilize for 30 seconds before initiating plasma at 100 Wfor 3 minutes. The chamber was then vented to atmosphere and lensesremoved. Lenses were then used within 1 hour. The PEG macromer solutionsof Example 4 were combined with excess TEOA to obtain solutions with atotal solids concentration of 0.1% and 0.5% and with a 10% molar excessof VS (See quantities in table below). A 0% PEG solution was alsoprepared as a control. The volume of 0.2M TEOA detailed below was addedto individual plastic vials (McMaster Carr 4242T83); followed by thenoted volume of PEG-VS. The surface functionalized PureVision lenseswere added to this solution and vortexed. The PEG-SH was added and thesolution was again vortexed. The lenses were placed on a mixing tablefor 24 hrs. The lenses were transferred to new plastic vials containingPhosphate Buffered Saline (PBS) and placed on the mixing table for 24hrs. The lenses were transferred to glass jars and autoclaved (Tuttnauer3870 E) in a wet cycle at 250° F. for 30 min.

PEG Concentration 0.00% 0.1% 0.5% Volume (μL) PEG-VS 0.0 5.3 26.6 PEG-SH0.0 9.7 48.4 TEOA 1500 1485 1425 Total 1500 1500 1500

Example 29 Silicone Lenses Surface Activated to Enhance HydrogelAdhesion

Silicone lenses (NuSil, Med 6755) were functionalized with the plasmatreatment process of Example 28. In a 50 mL conical tube, the lenseswere placed in a 10% w/v divinyl sulfone solution with a sodiumbicarbonate buffer at pH 11 and vortexed. After 1 hr on a mixing table,the lenses were washed with 20 ml of deionized water (DI Water) andplaced back on the mixing table in 40 ml of DI water. After 1 hr, thiscycle was repeated once more and the lenses were placed in the fridgefor 8 hrs in 40 ml of DI water.

Example 30 Silicone Lenses Dip Coated to Obtain a Bulk Layer of PEG

Silicone lenses (NuSil, Med 6755) were functionalized, dip coated andautoclaved, in the 0%, 0.1%, and 0.5% PEG solutions per Example 28.

Example 31 PureVision Lenses Surface Activated and Dip Coated to Obtaina Bulk PEG Layer

Contact lenses (PureVision, balafilcon A) were functionalized with theplasma treatment process of Example 28. The lenses were placed into 400μL of 10% PEGVS, vortexed, and then positioned on the mixing table for 5minutes. Subsequently, the lenses were placed in 3 mL of 0.2M TEOA,vortexed, and set on the mixing table for 5 minutes. The lenses wereadded to a solution of 0.1% PEG in TEOA according to example 28. Thelenses were vortexed, stationed on the mixing table for 24 hrs, andautoclaved according to Example 28.

Example 32 PureVision Lenses Dip Coated with FITC-Maleimide Addition forPEG Layer Visualization

Contact lenses (PureVision, balafilcon A) were functionalized with theplasma treatment process of Example 28. The lenses were placed into 0.1%and 0.5% PEG solutions according to example 28. 5.1 μl of FITC-Maleimide@ 10 mg/mL was added to each of the solutions to visualize the PEGlayer. The solutions were vortexed and placed on a mixing table for 24hrs.

Example 33 PureVision Lenses Dip Coated to Obtain a Bulk Layer of PEGwith Shortened Wash Cycle

Contact lenses (PureVision, balafilcon A) were functionalized and coatedaccording to Example 28. After 24 hrs in the PEG solution, the lenseswere placed in vials containing PBS and placed on the mixing table for1.5 hrs. The lenses were placed in a second set of vials containing PBSand placed on the mixing table for 1.5 hrs. The lenses were autoclavedaccording to Example 28.

Example 34 PureVision Lenses Dip Coated in Ultra-Low Concentration PEGwith No Wash Cycle

Contact lenses (PureVision, balafilcon A) were functionalized with theplasma treatment process of Example 28. The macromer solutions ofExample 4 were combined with TEOA at 0.01% and 0.05% PEG. A 0% PEGsolution was also prepared as a control. The PureVision lenses wereadded to this solution and vortexed. The PEG-SH was added and thesolution was again vortexed. The lenses were autoclaved in individualplastic vials for 30 min at 250° F. without being washed and withoutbeing removed from the PEG solution.

PEG Concentration 0.00% 0.01% 0.05% Volume PEG-VS 0.0 0.53 2.66 (μL)PEG-SH 0.0 .97 4.84 TEOA 1500 1498.5 1492.5 Total 1500 1500 1500

Example 35 PureVision Lenses Dip Coated in Low Concentration PEG withImmediate Autoclave in Glass

Contact lenses (PureVision, balafilcon A) were functionalized and coatedaccording to Example 28. The lenses were placed in glass vials(McMaster-Carr 4417T48) containing 3 ml of PBS and autoclaved accordingto Example 28.

Example 36 PureVision Lenses Dip Coated and Extracted in IsopropanolAlcohol

Contact lenses (PureVision, balafilcon A) were functionalized and coatedat the 0% and 0.5% concentrations according to Example 28. The lenseswere placed on a mixing table for 18 hrs. The PEG solution was replacedwith pure isopropanol alcohol (IPA) and returned to the mixing table for1 hr. The IPA was switched and the lenses were washed for an additionalhour. The IPA was replaced with deionized water and the lenses werewashed for 1 hr. The water was replaced twice and the lenses were washedfor 30 min each time. The lenses were placed in PBS and autoclaved perExample 28.

Example 37 PureVision Lenses Dip Coated in Organic Solvents to ObtainBulk Layer of PEG

1 ml of pure TEOA was added to 40 ml of isopropyl alcohol (IPA) to makea 0.2M solution. Pure Methanol was added to IPA at 0.2M TEOA to create a50% solution. 1 ml of concentrated TEOA was dissolved into 40 ml of pureMethanol (MeOH) to form a MeOH at 0.2 Molar TEOA solution. Contactlenses (PureVision, balafilcon A) were functionalized with the plasmatreatment process of Example 28. The macromer solutions of Example 4were combined with the 50% MeOH and 50% IPA at 0.2M TEOA at 0.5% PEG. A0% PEG solution was also prepared as a control. The macromer solutionsof Example 4 were also combined with the MeOH at 0.2 M TEOA at 0.5% PEG.The volume of MeOH and IPA detailed below were added to individualplastic vials; the surface functionalized PureVision lenses were addedto the solution and vortexed. The PEG-VS and PEG-SH were added and thesolution but the solution was not vortexed due to the sensitivity of thelenses in solvents. The lenses were placed on a mixing table for 18 hrs.A washing series was utilized to remove the organic solvents; thesolutions were changed to pure IPA and the lens were placed on themixing table for 1 hr. The IPA was replaced with deionized (DI) waterand the lenses were placed on the mixing table for 1 hr. The DI waterwas replaced with PBS and the lenses were autoclaved per Example 28.

Example 38 PureVision Lenses with DVS Activation During IPA SolventExtraction

1 ml of 100% TEOA was added to 40 ml of isopropyl alcohol (IPA) to makea 0.2M solution. Contact lenses (PureVision, balafilcon A) werefunctionalized according to Example 28 and placed in 5 ml of IPA at 0.2MTEOA. Non-plasma treated and no-peg lenses were also prepared ascontrols. 7.5% DVS was added to each vial. The lenses were swirled inthe solution and then placed on the mixing table for 1 hour. The DVS wasdiscarded and 40 ml of IPA was added to each solution prior to placingthe lenses on the mixing table for 1 hour. The IPA was changed and thelenses were placed on the mixing table for 1 hr. The IPA was replacedwith 40 ml of deionized (DI) water and mixed for 1 hr. The DI water waschanged and the lenses were mixed for 1 hr. The lenses were dip coatedand autoclaved according to Example 28.

Example 39 PureVision Lenses with DVS Activation During MeOH SolventExtraction

1 ml of 100% TEOA was added to 40 ml of methanol alcohol (MeOH) to makea 0.2M solution. Contact lenses (PureVision, balafilcon A) werefunctionalized according to Example 28 and placed in 5 ml of MeOH at0.2M TEOA. Non-plasma treated and no-peg lenses were also prepared ascontrols. 7.5% DVS was added to each vial. The lenses were swirled inthe solution and then placed on the mixing table for 1 hour. The DVS wasdiscarded and 40 ml of IPA was added to each solution prior to placingthe lenses on the mixing table for 1 hour. The IPA was changed and thelenses were placed on the mixing table for 1 hr. The IPA was replacedwith 40 ml of deionized (DI) water and mixed for 1 hr. The DI water waschanged and the lenses were mixed for 1 hr. The lenses were dip coatedand autoclaved according to Example 28.

Example 40 PureVision Lenses Dip Coated in Methanol Solvent to Obtain aBulk Layer of PEG

Contact lenses (PureVision, balafilcon A) were functionalized accordingto Example 28. A MeOH at 0.2 Molar TEOA solution was made according toExample 39. The macromer solutions of Example 4 were combined with theMeOH at 0.2 M TEOA at 0.1%, 0.25% and 0.5% PEG. A 0% PEG solution wasalso prepared as a control. The volume of MeOH detailed below was addedto individual glass vials; followed by the noted volume of PEG-VS. Thesurface functionalized PureVision lenses were added to this solution andvortexed. The PEG-SH was added and the solution was again vortexed. Thelenses were placed on a mixing table for 24 hrs.

A MeOH washing cycle was developed and implemented: The MeOH at 0.2 MTEOA and PEG solution was replaced with pure MeOH and the lenses wereplaced on the mixing table for 1 hr. The MeOH was replaced with IPA andthe lenses were placed on the mixing table for 1 hr. The IPA wasreplaced with a solution consisting of 50% IPA and 50% DI water and thelenses were placed on the mixing table for 1 hr. The 50% solution wasreplaced with 100% DI water and the lenses were placed on the mixingtable for 1 hr. The DI water was replaced with Phosphate Buffered Saline(PBS) and autoclaved according to Example 28.

PEG Concentration 0.00% 0.1% 0.25% 0.5% Volume PEG-VS 0.0 5.3 13.25 26.6(μL) PEG-SH 0.0 9.7 24.25 48.4 MeOH at 0.2M TEOA 1500 1485 1462.5 1425Total 1500 1500 1500 1500

Example 41 Plasma Treatment Process

The setting for the plasma treatment process were tested and updated.The plasma treatment process used nitrogen gas, grade 5, in a plasmachamber (Plasma Etch PE-50) with settings: 150 mTorr set point, 200mtorr vacuum, 3 min, @ 100% RF power. Pressure was reduced to 200milliTorr with continuous flow of nitrogen gas at 2.5-5 standard cubiccentimeters per minute. The chamber was allowed to stabilize for 30seconds before initiating plasma at 100 W for 3 minutes. The chamber wasthen vented to atmosphere and lenses removed. Lenses were then usedwithin 1 hour.

Example 42 Lenses Extracted in Isopropanol Alcohol, Desiccated, and DipCoated

Lenses were placed in 1.5 ml of IPA and set on a mixing table for 18hrs. The IPA was switched and the lenses were washed for an additionalhour. The IPA was replaced with deionized water and the lenses werewashed for 1 hr. The water was replaced twice and the lenses were washedfor 30 min each time. The lenses were placed in a vacuum chamber and thechamber was evacuated using a pump (Mastercool, 6 cfm) for 24 hrs. Thelenses were functionalized and coated at the 0% and 0.5% concentrationsaccording to Example 28 with the plasma treatment process of Example 41.The PEG solution was replaced with deionized water and the lenses werewashed for 1 hr. The lenses were placed in PBS and autoclaved perExample 28.

Example 43 PureVision Lenses Dip Coated to Obtain a Bulk Layer of PEG

Example 28 was repeated using the plasma treatment process of Example41.

Example 44 PureVision Lenses Dip Coated in Low Concentration PEG withImmediate Autoclave in Glass

Example 36 was repeated using the plasma treatment process of Example41.

Example 45 PureVision Lenses Dip Coated in Organic Solvents to ObtainBulk Layer of PEG

Example 38 was repeated using the plasma treatment process of Example41.

Example 46 PureVision Lenses Dip Coated in Methanol Solvent to Obtain aBulk Layer of PEG

Example 40 was repeated using the plasma treatment process of Example41.

Example 47 PureVision Lenses Extracted in Isopropanol Alcohol,Desiccated, Dip Coated, with Immediate Autoclave

Contact lenses (PureVision, balafilcon A) were extracted, desiccated,and dip coated according to Example 42. Immediately after the dipcoating process the lenses were autoclaved while in the PEG solutionaccording to Example 28.

Example 48 Silicone Lenses Extracted in Isopropanol Alcohol, Desiccated,and Dip Coated

Silicone contact lenses (NuSil, Med 6755) were extracted, desiccated,dip coated and autoclaved according to Example 42.

Example 49 PureVision Lenses Extracted in Isopropanol Alcohol,Desiccated, and Dip Coated

Contact lenses (PureVision, balafilcon A) lenses were extracted,desiccated, dip coated and autoclaved according to Example 42.

Example 50 PureVision Lenses Dip Coated in Methanol Solvent with HeatedRotation to Obtain a Bulk Layer of PEG

Contact lenses (PureVision, balafilcon A) were functionalized usingoxygen gas in a plasma chamber (Plasma Etch PE-50) at settings: 200mTorr, 3 min, 100% RF power. The lenses were dip coated according toExample 40 and placed in a heated oven with rotation at 37 C for 24hours. The lenses were washed and autoclaved according to Example 40,but with the following shortened wash times: MeOH 2× quick swirls, IPA2×20 min, IPA:H20 (50:50) 20 min, H20 10 min, and PBS for autoclave.

Example 51 Silicone Lenses Dip Coated in Methanol Solvent with HeatedRotation to Obtain a Bulk Layer of PEG

Silicone contact lenses (NuSil, Med 6755) were functionalized usingoxygen gas in a plasma chamber (Plasma Etch PE-50) at settings: 200mTorr, 3 min, 100% RF power. The lenses were dip coated according toExample 40 and placed in a heated oven with rotation at 37° C. for 24hours. The lenses were washed and autoclaved according to Example 40,but with the following shortened wash times: MeOH 2× quick swirls, IPA2×20 min, IPA:H20 (50:50) 20 min, H20 10 min, and PBS for autoclave.

Example 52 PureVision Lenses Pre-Activated, Dip Coated in MethanolSolvent with Heated Rotation

Lenses (PureVision, balafilcon A) were functionalized using oxygen gasin a plasma chamber (Plasma Etch PE-50) at settings: 200 mTorr, 3 min,100% RF power. The lenses were pre-activated with PEG-VS or VS, dipcoated according to Example 40 and placed in a heated oven with rotationat 37 C for 24 hours. The lenses were washed and autoclaved according toExample 40, but with the following shortened wash times: MeOH 2× quickswirls, IPA 2×20 min, IPA:H20 (50:50) 20 min, H20 10 min, and PBS forautoclave.

Example 53 Silicone Lenses Dip Coated to Obtain a Bulk Layer of PEG

Example 30 was repeated using the plasma treatment process of Example41.

Example 54 PureVision Lenses Dip Coated to Obtain a Bulk Layer of PEGusing Oxygen Gas

Example 28 was repeated using oxygen gas, grade 5, during the plasmatreatment process.

Example 55 PureVision Lenses Plasma Treated and Dip Coated in HyaluronicAcid to Obtain a Bulk Layer

Contact lenses (PureVision, balafilcon A) were functionalized accordingto Example 28 with the addition hyaluronic acid (HA) at of 10 mg ofhyaluronic acid (HA). Lenses were added to this solution and placed onthe mixing table for 1 hr. The HA solution was replaced with DI waterand the lenses were placed on a mixing table for 1 hr. The water wasreplaced and the lenses were placed on a mixing table for 1 hr, 2additional times. The lenses were placed in individual plastic vialscontaining 3 ml-5 ml of PBS.

Example 56 PureVision Lenses Plasma Treated and Surface Activated withDVS in NaOH

Contact lenses (PureVision, balafilcon A) were functionalized accordingto Example 28. 0.5 ml of DVS was added to 4.5 ml of 0.5M SodiumBiCarbonate (NaOH). Lenses were added to this solution and placed on themixing table for 20 min. Lenses were also placed in 5 ml of NaOH ascontrols. The solution was replaced with DI water and the lenses wereplaced on the mixing table for 20 min. This step was repeated 2additional times.

Example 57 PureVision Lenses Plasma Treated and Dip Coated in HyaluronicAcid to Obtain a Bulk Layer with a FITC-Maleimide Addition for LayerVisualization

Contact lenses (PureVision, balafilcon A) were functionalized accordingto Example 28 and dip coated according to Example 55. 51 μl ofFITC-Maleimide was added to each of the solutions to visualize the PEGlayer. The lenses were washed and stored according to Example 55.

Example 58 PureVision Lenses Plasma Treated and Dip Coated in HyaluronicAcid in NaOH to Obtain a Bulk Layer

Contact lenses (PureVision, balafilcon A) were functionalized accordingto Example 28. 5 ml of HA was added to 45 ml of 10M NaOH. 5 ml of HA wasadded to 45 ml of DI water for a control. Lenses were added to thesesolutions and placed on the mixing table for 1 hr. The solutions werereplaced with DI water and the lenses were placed on the mixing tablefor 1 hr. The lenses were placed in individual plastic vials containing3 ml-5 ml of PBS.

Example 59 Silicone Lenses Plasma Treated then Encapsulated in PEGHydrogel

Silicone lenses (NuSil, Med 6755) were functionalized according toExample 28. Agar molds were prepared according to Example 4. Lenses wereencapsulated according to Example 10.

Example 60 PureVision Lenses Plasma Treated and Dip Coated in Low orHigh Molecular Weight PEG

Contact lenses (PureVision, balafilcon A) were functionalized usingmonofunctional polyethylene glycol, end functionalized in vinyl sulfone(mPEG-VS). mPEGs of 5 kDa and 20 kDa were used.

5% w/v total mPEG-VS solutions were prepared in triethanolamine buffer(TEOA) at pH 8.0 and then filter sterilized in a 0.45 micron PVDFfilter. A 0% PEG solution was also prepared as a control.

3 ml of PEG solution was added to individual plastic vials (McMaster Can4242T83). The surface functionalized PureVision lenses were added tothis solution and vortexed. The lenses were placed on a mixing table for24 hrs. The lenses were transferred to new plastic vials containingPhosphate Buffered Saline (PBS) and placed on the mixing table for 24hrs.

Example 61 Silicone Lenses Plasma Treated then Encapsulated in PEGHydrogel with a FITC-Maleimide Addition for PEG Layer Visualization

Silicone lenses (NuSil, Med 6755) were functionalized according toExample 28. Agar molds were prepared according to Example 4. 5.1 μl ofFITC-Maleimide was added to each of the solutions to visualize the PEGlayer. Lenses were encapsulated according to Example 10.

Example 62 Oaysys Lenses Desiccated and Plasma Treated then Encapsulatedin PEG Hydrogel

Contact lenses (Acuvue Oaysys, senofilcon A) were desiccated accordingto Example 42 and functionalized according to Example 28. Agar moldswere prepared according to Example 4. Lenses were encapsulated accordingto Example 10.

Example 62 Lenses Encapsulated in PEG Hydrogel

Lenses (Lotrafilcon B) were functionalized according to Example 1. Agarmolds were prepared according to Example 4. Lenses were encapsulatedaccording to Example 10.

Example 63 Lenses Desiccated and Plasma Treated then Encapsulated in PEGHydrogel

Lenses (Lotrafilcon B) were desiccated according to Example 42 andfunctionalized according to Example 28. Agar molds were preparedaccording to Example 4. Lenses were encapsulated according to Example10.

Example 64 Silicone Lenses Plasma Treated and Dip Coated in Low or HighMolecular Weight PEG

Silicone lenses (NuSil, Med 6755) were functionalized according toExample 28, with the addition of a non-plasma treated control, and dipcoated according to Example 60.

Example 65 PureVision Lenses Plasma Treated then Encapsulated in PEGHydrogel

Contact lenses (PureVision, balafilcon A) were functionalized accordingto Example 28. Agar molds were prepared according to Example 4. Lenseswere encapsulated according to Example 10.

Example 66 PureVision Lenses Dip Coated to Obtain a Bulk Layer of PEG

Contact lenses (PureVision, balafilcon A) were functionalized and coatedaccording to Example 28. The lenses were washed according to example 33and autoclaved according to Example 28.

Example 67 Glucose Loading of Hydrogel Contact Lenses

Hydrogel contact lenses containing acrylate groups on the surface wereincubated in d-Glucose solution (10 mL/lens) for at least 4 hours. Theglucose concentration may range from 0.1 mM to 25 mM.

Example 68 PureVision Lenses Dip Coated and Accelerated Life Tested toIdentify the Stability of the Bulk Layer of PEG

Example 46 was repeated; contact lenses (PureVision, balafilcon A) dipcoated in methanol solvent to obtain a bulk layer of peg. Post autoclaveprocess according to Example 28, the lenses were tested according toExample 25. The lenses were placed in PBS and autoclaved once moreaccording to Example 28 or placed in sterile saline (Walgreens—SterileSaline Solution). The lenses were placed in hybridization ovens (StovallLife Science Inc) at 20, 40, or 60 degrees Centigrade. The lenses weretested on dates that correspond to six or twelve months of acceleratedlife testing as detailed by FDA 510K clearance requirements for medicaldevices generally, and daily wear contacts specifically. Post testing,the sterile saline was replaced with new sterile saline and the lenseswere replaced in the respective hybridization oven. Lot numbers withcorresponding solutions and temperatures are detailed below.

0% PEG n = 6 Storage Solution Temp [C.] Saline Sterile Saline 20 M167M170 45 M168 M171 60 M169 M172

0.5% PEG n = 6 Storage Solution Temp [C.] Saline Sterile Saline 20 M173M176 45 M174 M177 60 M175 M178

Example 69 MJS Lenses Dip Coated to obtain a Bulk Layer of PEG

MJS Lenses (MJS Lens Technology Ltd, Standard Product, 55% watercontent) were functionalized according to Example 41, coated andautoclaved according to Example 28, and tested according to Example 25.The lenses were then placed in hybridization ovens (Stovall Life ScienceInc) at 60 degrees Celsius for 7 days. The sterile saline(Walgreens—Sterile Saline Solution) was replaced and the lenses wereretested according to Example 25.

Example 70 Determining Water Content of Poly(Ethylene Glycol) CoatedContact Lenses Utilizing Mass Balance

This example illustrates how to determine the water content of a contactlens of the invention. In an effort to determine the potential watercontent of the polyethylene-glycol layer(s) of the contact lenses of theinvention, samples consisting of the layer components are prepared forevaluation. The resulting gels are then hydrated and tested to determinewater content.

PEG hydrogel macromer solutions as described in Example 5 were pipettedbetween two hydrophobic glass slides separated by a 1 mm spacer andallowed to incubate at 37° C. for 1 hour.

Hydrated samples were blotted dry and the mass at hydrated state wasrecorded via mass balance. Following the recording of the mass athydrated state, the samples were all dried under a vacuum of <1 inch Hgovernight.

Dried samples were removed from the vacuum oven after overnight dryingand then measured to record dry mass. Water content was calculated usingthe following relationship: Water content=[(wet mass-dry mass)/wetmass]×100%

Example 71 Preparation of Poly(ethylene glycol) Hydrogel MacromerSolutions

In one example, the PEG hydrogel consists of two components. The firstis 8-arm, 10 kDa poly(ethylene glycol) (PEG) end functionalized withvinyl sulfone (PEG-VS). The second is 4-arm, 10 kDa PEG endfunctionalized with thiol groups (PEG-SH). The PEG-VS was dissolved to10% w/v in triethanolamine buffer (TEOA) at pH 8.0 and then filtersterilized in a 0.45 micron PVDF filter. The PEG-SH was dissolved to 10%w/v in distilled water and then filter sterilized in a 0.45 micron PVDFfilter.

Example 72 Contact Lenses

In another example, the following lenses and materials were eachprocessed through the subsequent examples: Silicone (NuSil, Med 6755);PureVision, balafilcon A; Acuvue Oaysys, senofilcon A; AIR OPTIX,Lotrafilcon B, MJS Lenses, MJS Lens Technology Ltd. All subsequentreferences to ‘lenses’, include each of the above lenses and materials.

Example 73 Contact Lenses Dip Coated to Obtain a Bulk Layer ofPoly(ethylene glycol) (PEG) Hydrogel

In another example, commercially available and hydrated lenses werewashed in deionized water three times for 30 min each time. The lenseswere desiccated in a vacuum chamber for 2-24 hrs.

Lens surfaces were functionalized using nitrogen gas in a standardplasma chamber (Plasma etch PE-50) at settings: 200 mTorr, 3 min, 100 WRF power, 5-20 standard cubic centimeters per minute. Lenses were thenused within 1 hour.

The PEG macromers were combined with either deionized water (DI Water),Isopropanol Alcohol (IPA), or Methanol (MeOH) @ 0.2M TEOA to obtainsolutions with a total solids concentration of 0.1%, 0.25% and 0.5%.Various concentrations of substrates were used; each solution was at a10% molar excess of VS (See quantities in table below) and a 0% PEGsolution was also prepared as a control.

The volume of substrate detailed below was added to individual vials,followed by the noted volume of PEG-VS. The surface functionalizedlenses were added to this solution. The PEG-SH was added and the lenseswere placed on a mixing table for 1 hr-24 hrs. The lenses were washedindividually in the corresponding substrate for 30 min. For the solventconditions, consecutive 30 min washes were in 100% IPA, 50% IPA in DIWater, and 100% DI Water. Lenses in the aqueous substrate were onlywashed in 100% DI water.

The lenses were placed in Phosphate Buffered Saline (PBS) and autoclavedin a wet cycle at 250° F. for 30 min. Lens general comfort and contactangle were determined through wear and direct in-house measurement,respectively.

PEG Concentration 0.00% 0.1% 0.25% 0.5% Volume PEG-VS 0.0 5.3 13.25 26.6(μL) PEG-SH 0.0 9.7 24.25 48.4 DI H20, IPA, or MeOH 1500 1485 1462.51425 @ 0.2M TEOA Total 1500 1500 1500 1500

Example 74 Lenses Dip Coated with Recycled PEG

In another example, the steps of above Example 73 were repeated forcontact lenses PureVision, balafilcon A, at a 0.4M concentration ofTEOA. The PEG from this process was kept. After 24 hrs, a PEG solutionwas developed using 50% of the original (750 μL) and 50% fresh ornon-previously-used PEG. Example 73 was repeated using this PEGsolution.

Example 75 Lenses Surface Activated Using Hydrogen Peroxide and DipCoated

In another example, dehydrated contact lenses PureVision, balafilcon A,were placed in commercially available Hydrogen Peroxide for 1 hr. Thelenses were washed with DI water for 30 min. The coating, washing,autoclave, and testing process was repeated according to Example 73.

Example 76 Lenses Extracted, Desiccated, and Dip Coated

In another example, lenses were placed in 1.5 ml of IPA or MeOH(solvent) and set on a mixing table for 12-18 hrs. The solvent wasswitched and the lenses were washed in the corresponding solvent for anadditional hour. The solvent was replaced with deionized water and thelenses were washed three times for 30 min to 1 hr each time. The lenseswere desiccated in a vacuum chamber for 2-24 hrs.

Lens surfaces were functionalized using nitrogen gas in a standardplasma chamber (Plasma etch PE-50) at settings: 200 mTorr, 3 min, 100 WRF power, 5-20 standard cubic centimeters per minute. Lenses were thenused within 1 hour. The lenses were coated, washed, autoclaved, andtested according to the aqueous process of Example 73.

Example 77 Lenses Dip Coated and Accelerated Life Tested to Identify theStability of the Bulk Layer of PEG

In another example, the steps of Example 73 were repeated; for contactlenses (PureVision, balafilcon A and MJS Lens Technology Ltd). Postautoclave and testing process, the lenses were placed in PBS andautoclaved once more or placed in sterile saline. The lenses were placedin hybridization ovens (Stovall Life Science Inc) at 20, 40, or 60degrees Centigrade. The lenses were tested on dates that correspond tosix or twelve months of accelerated life testing as detailed by FDA 510Kclearance requirements for medical devices generally, and daily wearcontacts specifically. Post-testing, the sterile saline was replacedwith new sterile saline and the lenses were replaced in the respectivehybridization oven.

Example 78 Coating Characterized via Captive Bubble Contact AngleTesting

In another example, to measure lens contact angles, the captive bubbletechnique was used. The lens was loaded onto a small plate with abulbous feature. The lens was submerged in PBS and suspended atop aplate that has a hole through which the convex surface of the lensprotrudes downward. A blunt needle was placed just below the surface ofthe center of the lens. A bubble was then advanced with a syringe pumpuntil it makes contact with the lens, at which point the bubble wasretracted until it breaks free from either the lens or the needle.Through a magnifying lens, a high-definition video camera records theentire procedure, after which an image was saved from the frameimmediately preceding the moment the bubble detaches from either thelens or the needle. From this image, the angles between the lens and thebubble on both sides of the bubble were calculated in MATLAB and savedas the contact angles for that lens.

Example 79 Lubricity Test Method

A test method was designed and built to observe the affects that thehydrogel coating has on the lubricity of the lens. Three contact lenseswere used in this evaluation:

1. Packaged silicone hydrogel lens A

2. Hydrogel coated silicone hydrogel lens A

3. Packaged silicone hydrogel lens B 6 sec

A borosilicate glass plate was cleaned and submerged in a tank of PBS.One end of the plate was raised 30 mm with a shim to create a ramp withan angle of ˜11 degrees. The test lenses were placed at the top of theramp and weighted down with a stainless steel bolt, weightingapproximately 1.13 grams. The lenses were allowed to slide down the ramp˜152 mm and the time required to reach the bottom of the ramp wasrecorded. Results:

Lens Type Time to Slide (sec) Packaged silicone hydrogel lens A Lensallowed to slide for X seconds but only slid down X mm Hydrogel coatedsilicone hydrogel lens A 2 second Packaged silicone hydrogel lens B 6sec 6 seconds

The results of the tests demonstrate a significant increase in lubricityof the lens coated with hydrogel as compared with the uncoated control.

As used herein in the specification and claims, including as used in theexamples and unless otherwise expressly specified, all numbers may beread as if prefaced by the word “about” or “approximately,” even if theterm does not expressly appear. The phrase “about” or “approximately”may be used when describing magnitude and/or position to indicate thatthe value and/or position described is within a reasonable expectedrange of values and/or positions. For example, a numeric value may havea value that is +/−0.1% of the stated value (or range of values), +/−1%of the stated value (or range of values), +/−2% of the stated value (orrange of values), +/−5% of the stated value (or range of values), +/−10%of the stated value (or range of values), etc. Any numerical rangerecited herein is intended to include all sub-ranges subsumed therein.

As for additional details pertinent to the present invention, materialsand manufacturing techniques may be employed as within the level ofthose with skill in the relevant art. The same may hold true withrespect to method-based aspects of the invention in terms of additionalacts commonly or logically employed. Also, it is contemplated that anyoptional feature of the inventive variations described may be set forthand claimed independently, or in combination with any one or more of thefeatures described herein. Likewise, reference to a singular item,includes the possibility that there are plural of the same itemspresent. More specifically, as used herein and in the appended claims,the singular forms “a,” “and,” “said,” and “the” include pluralreferents unless the context clearly dictates otherwise. It is furthernoted that the claims may be drafted to exclude any optional element. Assuch, this statement is intended to serve as antecedent basis for use ofsuch exclusive terminology as “solely,” “only” and the like inconnection with the recitation of claim elements, or use of a “negative”limitation. Unless defined otherwise herein, all technical andscientific terms used herein have the same meaning as commonlyunderstood by one of ordinary skill in the art to which this inventionbelongs. The breadth of the present invention is not to be limited bythe subject specification, but rather only by the plain meaning of theclaim terms employed.

What is claimed is:
 1. A coated contact lens comprising: a lens corecomprising an outer surface; and a hydrogel layer covalently attached toat least a portion of the outer surface, the hydrogel layer adapted tocontact an ophthalmic surface, wherein the hydrogel layer comprises ahydrophilic polymer population having a first PEG species and a secondPEG species, the first PEG species being at least partially cross-linkedto the second PEG species.
 2. The lens of claim 1, wherein the hydrogellayer and core are covalently attached at the outer surface by asulfonyl moiety.
 3. The lens of claim 1, wherein the hydrogel layer andcore are covalently attached at the outer surface by an alkylenesulfonyl moiety.
 4. The lens of claim 1, wherein the hydrogel layer andcore are covalently attached at the outer surface by a dialkylenesulfonyl moiety.
 5. The lens of claim 1, wherein the hydrogel layer andcore are covalently attached at the outer surface by an ethylenesulfonyl moiety.
 6. The lens of claim 1, wherein the hydrogel layer andcore are covalently attached at the outer surface by a diethylenesulfonyl moiety.
 7. The lens of claim 1, wherein the hydrogel layer andcore are covalently attached at the outer surface by a thioether moiety.8. The lens of claim 1, wherein the hydrogel layer and core arecovalently attached at the outer surface by a sulfonyl moiety and athioether moiety.
 9. The lens of claim 1, wherein the first PEG speciescomprises a reactive sulfonyl group and the second PEG species comprisesa reactive thiol, and the first PEG species and second PEG species arecross-linked by a thioether linkage.
 10. The lens of claim 1, whereinthe hydrogel layer substantially surrounds the outer surface of thecore.
 11. The lens of claim 1, wherein the hydrogel layer and core aresubstantially optically clear.
 12. The lens of claim 1, wherein thehydrogel layer is adapted to allow optical transmission through thehydrogel layer to the ophthalmic surface.
 13. The lens of claim 1,wherein the hydrogel layer comprises a thickness between about 50 nm toabout 500 nm.
 14. The lens of claim 1, wherein the hydrogel layercomprises a thickness below about 100 nm.
 15. The lens of claim 1,wherein the hydrogel layer comprises a maximum thickness of about 10microns.
 16. The lens of claim 1, wherein a first portion of thehydrogel layer comprises a first thickness different from a secondthickness of a second portion of the hydrogel layer.
 17. The lens ofclaim 1, wherein each of the first and second PEG species is a branchedspecies having a branch count between two to twelve branch arms.
 18. Thelens of claim 1, wherein the first PEG species comprises a reactiveelectron pair accepting group and the second PEG species comprises areactive nucleophilic group, the reactive electron pair accepting groupand the reactive nucleophilic group adapted to react to thereby formcross-links between the first PEG species to the second PEG species. 19.The lens of claim 18, wherein the reactive electron pair accepting groupis a sulfone moiety.
 20. The lens of claim 18, wherein the reactivenucleophilic group is a thiol moiety.
 21. The lens of claim 18, whereinthe reactive electron pair accepting group of the first PEG species iscovalently linked to the outer surface of the core.
 22. The lens ofclaim 1, further comprising an advancing contact angle between about 20degrees to about 50 degrees.
 23. The lens of claim 1, further comprisingan advancing contact angle between about 25 degrees to about 35 degrees.24. The lens of claim 1, wherein the hydrogel layer comprises betweenabout 80% to about 98% water by weight.
 25. The lens of claim 1, whereinthe core consists of silicone.
 26. The lens of claim 1, wherein the corecomprises silicone.
 27. The lens of claim 1, wherein the core issubstantially free of silicone.
 28. The lens of claim 1, wherein thecore comprises a hydrogel.
 29. A multi-layer contact lens comprising alens core layer covered by an outer hydrophilic PEG polymer layer,wherein the hydrophilic polymer layer comprises a first PEG macromersubpopulation having an electron pair accepting moiety and a second PEGmacromer subpopulation having a first nucleophilic reactive moiety,wherein the first and second PEG macromer subpopulations arecross-linked.
 30. The lens of claim 29, wherein the hydrophilic polymerlayer is attached to the core layer by a covalent linkage between theelectron pair accepting moiety of the first PEG macromer and a secondnucleophilic reactive moiety on a surface of the core layer.
 31. Thelens of claim 30, wherein the covalent linkage between the core layerand the electron pair accepting moiety is a thioether moiety.
 32. Thelens of claim 29, wherein the concentration of the electron pairaccepting moiety exceeds the concentration of the first nucleophilicreactive moiety by about 1% to about 30%.
 33. The lens of claim 29,wherein the concentration of the electron pair accepting moiety exceedsthe concentration of the first nucleophilic reactive moiety by about 5%to about 20%.
 34. The lens of claim 29, wherein the electron pairaccepting moiety is a sulfonyl group.
 35. The lens of claim 29, whereinthe first nucleophilic reactive moiety is a thiol group.
 36. The lens ofclaim 29, wherein the hydrophilic polymer layer comprises one or morespecies of a branched PEG polymer.
 37. The lens of claim 36, wherein thebranched PEG polymer species comprises a branch count between about twoarms to about twelve arms.
 38. The lens of claim 36, wherein thebranched PEG polymer species comprises starred branching.
 39. The lensof claim 29, wherein each of the first and second PEG macromers has amolecular weight between about 1 kDa and about 40 kDa.
 40. The lens ofclaim 39, wherein the molecular weight is between about 5 kDa and about30 kDa.
 41. The lens of claim 29, wherein the hydrophilic PEG layercomprises between about 80% and about 98% water by weight.
 42. The lensof claim 29, wherein the hydrophilic PEG layer comprises between about85% and about 95% water by weight.
 43. The lens of claim 29, wherein thehydrophilic PEG layer has a thickness less than about 1 micron.
 44. Thelens of claim 29, wherein the hydrophilic PEG layer has a thickness lessthan about 5 micron.
 45. The lens of claim 29, wherein the hydrophilicPEG layer has a maximum thickness of about 10 microns.
 46. The lens ofclaim 29, wherein the hydrophilic PEG layer has a maximum thicknessbetween about 1 micron to about 5 microns.
 47. The lens of claim 29,wherein the hydrophilic PEG layer has a thickness between about 50 nm toabout 500 nm.
 48. The lens of claim 29, wherein the hydrophilic PEGlayer has a thickness between about 100 nm to about 250 nm.
 49. The lensof claim 29, wherein the hydrophilic PEG layer further comprises atleast one active agent.
 50. The lens of claim 49, wherein the at leastone active agent is selected from the group consisting of a UV-absorbingagent, a visibility tinting agent, an antimicrobial agent, a bioactiveagent, a leachable lubricant, a leachable tear-stabilizing agent, or anymixture thereof.
 51. The lens of claim 29, wherein the core layerconsists of silicone.
 52. The lens of claim 29, wherein the core layercomprises silicone.
 53. The lens of claim 29, wherein the core layer issubstantially free of silicone.
 54. A method of making a PEG hydrogelcoated contact lens comprising: reacting an outer surface of the contactlens with a first PEG species of a hydrophilic polymer solution, whereinthe first PEG species comprises an electron pair accepting moiety and afirst portion of the electron pair accepting moiety forms a covalentattachment to the outer surface of the contact lens through a firstnucleophilic conjugate reaction; and reacting the first PEG species ofthe hydrophilic polymer solution with a second PEG species of thehydrophilic polymer solution, the second PEG species comprising anucleophilic reactive moiety adapted to covalently link to a secondportion of the electron pair accepting moiety of the first PEG speciesin a second nucleophilic conjugate reaction to thereby at leastpartially cross-link the first and second PEG species, wherein a PEGhydrogel coating is formed and covalently attached to the outer surfaceof the contact lens by the first and second nucleophilic conjugatereactions.
 55. The method of claim 54, further comprising modifying anouter surface of a contact lens to form the plurality of reactivenucleophilic sites on the outer surface.
 56. The method of claim 55,wherein the modifying step comprises exposing the outer surface of thecontact lens to a gas plasma treatment.
 57. The method of claim 55,wherein reacting an outer surface of the contact lens with the first PEGspecies comprises reacting at least a portion of the plurality ofreactive nucleophilic sites on the outer surface with the first portionof the electron pair accepting moiety on the first PEG species.
 58. Themethod of claim 54, wherein both of the first and second nucleophilicconjugate reactions are 1,4-nucleophilic addition reactions.
 59. Themethod of claim 54, wherein the first and second nucleophilic conjugatereactions are both a Michael-type reaction.
 60. The method of claim 54,wherein both of the first and second nucleophilic conjugate reactionsare click reactions.
 61. The method of claim 54, wherein thenucleophilic reactive moiety of the second PEG species is a thiol groupand the electron pair accepting moiety of the first PEG species is asulfone group.
 62. The method of claim 54, wherein the first PEG speciesand the second PEG species are cross-linked through a thioether moiety.63. The method of claim 54, wherein the hydrophilic polymer solutioncomprises substantially equivalent concentrations of the first andsecond PEG species.
 64. The method of claim 54, wherein theconcentration of the electron pair accepting moiety of the first PEGspecies exceeds the concentration of the nucleophilic reactive moiety ofthe second PEG species by about 1% to about 30%.
 65. The method of claim54, wherein the concentration of the electron pair accepting moiety ofthe first PEG species exceeds the concentration of the nucleophilic PEGreactive moiety of the second PEG species by about 5% and about 20%. 66.The method of claim 54, wherein the reacting steps are performed at atemperature between about 15 degrees Celsius and about 100 degreesCelsius.
 67. The method of claim 54, wherein the reacting steps areperformed at a temperature between about 20 degrees Celsius and about 40degrees Celsius
 68. The method of claim 54, wherein the reacting stepsare performed at a pH between about 7 and about
 11. 69. The method ofclaim 54, wherein the PEG hydrogel coating is substantially opticallyclear.
 70. The method of claim 54, wherein the contact lens comprises acore consisting of silicone.
 71. The method of claim 54, wherein thecontact lens comprises a core comprising silicone.
 72. The method ofclaim 54, wherein the contact lens comprises a core substantially freeof silicone.
 73. The method of claim 72, wherein the contact lenscomprises a hydrogel core.